2021/22 Seminars

14/12 Dr Anaelle Dumas, Current tools to interrogate microglia biology in brain tumours

Neurogenomics seminar

14 December, 15:00-16:00

Dr Anaelle Dumas

University of Freiburg

"Current tools to interrogate microglia biology in brain tumours"

Microglial cells perform a plethora of functions in the central nervous system (CNS), which have emerged as particularly critical in the development and progression of brain tumours. As the prominent immune cell type in the tumour microenvironment, microglia tumour-associated profile and activity has become a major focus in the field. Significant technical advancements have prompted the development of novel systems adapted to analyze microglia with increasing specificity and intricacy. The advent of single-cell technologies combined with targeted mouse models has been decisive in deciphering microglia phenotypic and functional heterogeneity. However sophisticated these tools have become, clear limitations remain. Understanding their pitfalls and advantages ensures their correct application. Therefore, we provide a guide to the cutting-edge methods currently available to dissect microglial biology.

2/12 Julieta Camino De La Llosa, Can people with dementia perform tasks in a new environment

Virtual Brain Meeting Seminar

2nd December 2021 4-5pm

Julieta Camino De La Llosa

University of East Anglia

A different and tidier kitchen: can people with dementia perform tasks in a new environment?

30/11 Dr Nina Dräger,CRISPRi/a in iPSC-derived microglia uncovers regulators of disease

Neurogenomics seminar

30th november 2021

Dr Nina Dräger

UCSF

"A CRISPRi/a platform in iPSC-derived microglia uncovers regulators of disease states"

Microglia are emerging as key drivers of neurological diseases. However, we lack a systematic understanding of the underlying mechanisms. In this talk, I present a screening platform to systematically elucidate functional consequences of genetic perturbations in human iPSC-derived microglia. We developed an efficient eight-day protocol for the generation of microglia-like cells based on the inducible expression of six transcription factors. We established inducible CRISPR interference and activation in this system and conducted three screens targeting the “druggable genome”. These screens uncovered genes controlling microglia survival, activation, and phagocytosis, including neurodegeneration-associated genes. A screen with single-cell RNA sequencing as the readout revealed that these microglia adopt a spectrum of states mirroring those observed in human brains and identified regulators of these states. A disease-associated state characterized by SPP1 expression was selectively depleted by CSF1R inhibition. Thus, our platform can systematically uncover regulators of microglia states, enabling their functional characterization and therapeutic targeting.

16/11 Dr Greg Findlay, Linking Variants to Functional Effects with Saturation Genome Editing

Neurogenomics Seminar

16th November, 3-4pm

Dr Greg Findlay

Francis Crick Institute

'Linking Variants to Functional Effects with Saturation Genome Editing'

Our incomplete understanding of how rare variants contribute to disease phenotypes substantially limits the clinical utility of genetic data. To help address the challenge of variant interpretation, we’ve developed a CRISPR/Cas9-based approach called saturation genome editing (SGE) in which we engineer and assay all possible single nucleotide variants across targeted genomic regions. In this talk, I will describe the optimisation of SGE and its application to study ~5,000 variants in the tumour suppressor BRCA1. The resulting functional data reveal the diverse genetic mechanisms through which variants exert phenotypic effects and predict with high accuracy which variants predispose patients to cancer. Ongoing work in the laboratory centres on scaling SGE and related technologies to enable systematic interrogation of variants across many additional disease loci. 

Zoom meeting ID    814 1666 7061
Password                 124233  
https://ukdri.zoom.us/j/81416667061?pwd=Um5GTmZlZ2w0SnNSSnppV3hyNDJHdz09

 

2/11 Dr Renzo Mancuso, Human microglia xenotransplantation models

Neurogenomics Seminar

5th November 2021- 3-4pm

Dr Renzo Mancuso

VIB – University of Antwerp

"Human microglia xenotransplantation models to study genetic risk for neurodegeneration"

Neuroinflammation and microglial activation are significant processes during Alzheimer’s disease (AD) pathology. Recent transcriptomic profiling from experimental AD models sheds light on the changes undergone by microglia during the pathological process in mice. Nevertheless, determining the role of microglia in human AD comes with technical challenges, including lack of homology between mouse and humans, and limited expression of AD risk genes in mouse microglia. To address this important question, we have generated a novel model of human-mouse chimera that consist of the engraftment of iPSC-derived human microglia into the mouse brain. We first validated this model by comparing the gene expression profile of iPSC-derived to primary human microglia isolated from surgical resected tissue and investigated the response of iPSC-derived microglia to oligomeric Aβ in vivo. We also investigated the role of different genetic risk factors in human microglia in vivo. We found that altering microglial genetics affects the response of human microglia to amyloid beta plaques, with significant changes in their phenotypic transition from homeostatic to activation states. This novel platform will help us to understand the role of human microglia in AD and will give insights into the potential of new therapeutic routes based on the modulation of microglia and neuroinflammation. 

19/10 Tara Chari, The Specious Art of Single-Cell Genomics

Neurogenomics Seminar

19th October- 4-5pm

Tara Chari

California Institute of Technology

"The Specious Art of Single-Cell Genomics"

Dimensionality reduction is standard practice for filtering noise and identifying relevant dimensions in large-scale data analyses. In biology, single-cell expression studies almost always begin with reduction to two or three dimensions to produce ‘all-in-one’ visuals of the data that are amenable to the human eye, and these are subsequently used for qualitative and quantitative analysis of cell relationships. However, there is little theoretical support for this practice. We examine the theoretical and practical implications of low-dimensional embedding of single-cell data, and find extensive distortions incurred on the global and local properties of biological patterns relative to the high-dimensional, ambient space. In lieu of this, we propose semi-supervised dimension reduction to higher dimension, and show that such targeted reduction guided by the metadata associated with single-cell experiments provides useful latent space representations for hypothesis-driven biological discovery.

5/10 Dr Hamish King, Mapping dynamic cell states and gene regulatory networks

Neurogenomics seminar

5 October, 15:00-16:00

Dr Hamish King

"Mapping dynamic cell states and gene regulatory networks with single-cell genomics: lessons from the immune system"

B cell-mediated immune responses and memory form in secondary lymphoid organs, such as the tonsils, lymph nodes or spleen and form a major arm of the adaptive immune system to fight and remember infections. During this process, B cells undergo affinity maturation in the germinal centre reaction before differentiation into memory or plasma cells. However, many questions remain about the dynamic cellular states involved, including the gene regulatory networks that underlie key cell fate decisions and phenotypes. We generated a comprehensive roadmap of humaueiran B cell maturation in a model secondary lymphoid organ by defining the gene expression, antibody repertoires, and chromatin accessibility of diverse B cell states at single-cell resolution. We reconstruct gene expression and transcription factor dynamics during B cell activation to identify a novel pre-germinal centre state and use spatial transcriptomics to map this population in human tissue. Finally, we leverage our single cell transcriptomic and epigenomic maps to interpret potential regulatory impact of genetic variants implicated in autoimmunity. We find that many autoimmune-linked fine-mapped GWAS variants exhibit their greatest regulatory potential in germinal centre-associated cell populations, providing new insights into the cellular and genetic causes that may underpin autoimmune disease.

Zoom meeting ID      837 2803 4677
Password                     842186
https://ukdri.zoom.us/j/83728034677?pwd=NFVSUVp3MENvdXkrVGNEMU1JN2RWdz09

21/9 Dr Claudia Han, Decoding of gene regulatory networks

Neurogenomics seminar

21st September, 4-5pm

Dr Claudia Han

"Decoding of gene regulatory networks underlying human microglia maturation"

Microglia, as the resident macrophages of the brain, engage in a variety of processes essential for brain development and homeostasis. In the human brain, microglia infiltrate the fetal brain as early as the fourth gestational week with microglia colonization of the brain preceding waves of neuro-, astro-, and oligodendro-genesis, myelination, etc, suggesting an ever-evolving environmental milieu that can influence cellular phenotypes. Many lines of evidence indicate that mis-regulation of microglia functions contributes to the pathogenesis of neurodegenerative diseases and in neurodevelopment disorders. Here, utilization of both bulk and single-cell assessment of gene expression and open chromatin profiles between human fetal and postnatal microglia reveal that changing brain environmental signals have a significant impact on the maturing transcriptome and predicted gene regulatory network of human microglia during development. Additionally, development of a new computational approach that integrates epigenomic and single-cell RNA-seq data allows the decoding of cellular heterogeneity with inference of subtype- and development stage-specific transcriptional regulators. Lastly, our collective data integrated with existing iPSC-microglia models provide a roadmap for the interrogation of human fetal and postnatal microglia phenotypes in the future. 

Zoom meeting ID      820 9289 0565
Password                     522151
https://ukdri.zoom.us/j/82092890565?pwd=emNTMndsVFgvMEdad3VCM1NKV2VhUT09

2020/21 Seminars

Dr Topher Hübel, Genetics of eating disorders

Neurogenomics seminar

13 July, 15:00-16:00

Dr Topher Hübel

King’s College London 

"Genetics of eating disorders, behaviours, and cognitions"

Eating disorders (ED), including anorexia nervosa (AN), bulimia nervosa (BN), and binge-eating disorder (BED), are severe and complex psychiatric disorders with life-long effects on mental and physical health (Treasure et al., 2015). Current treatment options have limited effectiveness (Brownley et al., 2016; Himmerich& Treasure, 2018), highlighted by the observation that only 30% of adult patients with AN fully recover (Steinhausen, 2009). The development of EDs is complex and driven by both environmental and genetic factors (Bulik et al., 2019; Weissman, 2019). Previous research shows that eating disorders run in families (Lilenfeld et al., 1998), but the specific genetic variants associated with risk for EDs are not well understood (Breithaupt et al., 2018; Hübel et al., 2019). Twin studies estimate the heritability of EDs to be between 40%-70% (Thornton et al., 2011). Similar to other psychiatric disorders, such as depression (Wray et al., 2018) or schizophrenia (Schizophrenia Working Group of the Psychiatric Genomics Consortium et al., 2014), many genetic variants with relatively small effect are likely to underlie the overall genetic risk for AN (Duncan et al., 2017; Watson et al., 2019). The talk will summarise current findings on genomics of EDs and related behaviours in cross-sectional and longitudinal samples.

Dr Marek Bartosovik, Single-cell CUT&Tag profiling

Neurogenomics seminar

29 June, 15:00-16:00

Dr Marek Bartosovic

Karolinska Institute

"Single-cell CUT&Tag profiling of histone modifications in the mouse brain"

Profiling of DNA accessibility at the single-cell level using scATAC-seq is becoming standard in uncovering epigenetic heterogeneity of complex samples. However, modified histones are known to be more difficult to profile at the single-cell level. We have recently developed and adopted the scCUT&Tag method to the 10x Genomics chromium platform. scCUT&Tag uses antibody-directed tagmentation by hyperactive Tn5 transposase and commercially available microfluidic platform. The method can be used at high throughput to profile tens of thousands of single nuclei for both active and repressive histone modifications and does not require any custom equipment. 

We have applied scCUT&Tag to profile both active and repressive histone marks in the mouse central nervous system. The obtained single-cell histone profiles can be used to deconvolute the individual cell types in the brain and generate sub-population level epigenetic profiles. Moreover scCUT&Tag data provides unique insights into histone marks spreading during cell differentiation, promoter-enhancer interactions or promoter bivalency. scCUT&Tag can be applied to healthy or diseased tissue and will be instrumental in uncovering epigenetic heterogeneity and regulation of gene expression in dynamic processes. 

Brian Bigger, Actinomycin D, identified via high throughput screening

Department of Brain Sciences Seminar

21st June- 4-5pm

Professor Brian Bigger

The University of Manchester 

Actinomycin D, identified via high throughput screening, downregulates Sox2 and improves survival in preclinical models of recurrent glioblastoma”.

Dr Sarah Dick and Homaira Hamidzada, Cross-tissue organisation

Neurogenomics seminar

15 June, 15:00-16:00

Dr Sarah Dick and Homaira Hamidzada

University of Toronto

"Cross-tissue organization of resident macrophage subsets"

Resident macrophages orchestrate homeostatic, inflammatory and reparative activities. In addition to general macrophage functions, macrophages are highly adapted to their tissue of residence, driving transcriptional heterogeneity. Although less defined, macrophage subsets can co-exist within a single tissue, suggesting additional heterogeneity. Using unbiased single cell transcriptomics we reveal three macrophage subpopulations co-exist in steady state tissue in the murine and human heart, liver, lung, kidney and brain. Despite major tissue-specific differences, a conserved core transcriptional profile helped identify key developmental/biological similarities between macrophage subset across organs. Through a variety of fate mapping studies, we defined a common framework to identify and track tissue macrophage heterogeneity across organs, accounting for both transcriptional diversity and biological commonalities.

Dr William Lai, Screening of PCRP transcription

Neurogenomics Seminar

1 June, 15:00-16:00

Dr William Lai

Cornell University

"Screening of PCRP transcription factor antibodies in ChIP-exo"

Antibodies offer a powerful means to interrogate specific proteins in a complex milieu. However, antibody availability and reliability are problematic and epitope tagging can be impractical in many cases (e.g., human tissue, or cell lines from a wide variety of origins). In an effort to improve this situation, the Protein Capture Reagents Program (PCRP) generated over a thousand renewable monoclonal antibodies (mAbs) against human-presumptive chromatin proteins. However, these reagents have not been widely field-tested. We therefore performed a screen to test their ability to enrich genomic regions via chromatin immunoprecipitation (ChIP) and a variety of orthogonal assays. 887 unique antibodies against 681 unique human transcription factors (TFs), were assayed by ultra-high resolution ChIP-exo/seq generating ~1,200 ChIP-exo datasets, primarily in a single pass in one cell type (K562). About 5% of the tested antibodies displayed target (i.e., cognate antigen) enrichment across at least one assay and are strong candidates for additional validation. An additional 34% produced ChIP-exo data that was distinct from background and thus warrant further testing. The remaining 61% were not substantially different from background, and likely require consideration of a much broader survey of cell types and/or assay optimizations. We demonstrate and discuss the metrics and challenges to antibody validation in chromatin-based assays. We believe that the methodologies described here can be used as a framework not only for antibody validation, but also as the first step towards an automated and agnostic analysis platform for genomics.

 

Dr Stefano Berto, Imaging genomics of the human brain

Neurogenomics Seminar

18th May 4-5pm

Dr Stefano Berto 

Medical University of South Carolina

"Imaging genomics of the human brain: insights into the human memory"

Recently, imaging genomics has emerged as a powerful translational strategy to understand the molecular basis of macroscopic functional phenotypes measured across the brain. This strategy correlates genomic data with variation in one or more imaging-derived phenotypes. To shed light into the genomics that might influence human memory, we employed an imaging genomics approach based on intracranial electroencephalography recordings (iEEG) and defined genes that might support brain oscillations active during episodic memory. To do so, we measured memory-sensitive oscillations using intracranial electroencephalography recordings from the temporal cortex of patients performing an episodic memory task. When these patients subsequently underwent resection, we employed transcriptomics on the temporal cortex to link gene expression with brain oscillations and identified genes correlated with oscillatory signatures of memory formation across six frequency bands. A co-expression analysis isolated oscillatory signature-specific modules associated with neuropsychiatric disorders and ion channel activity, with highly correlated genes exhibiting strong connectivity within these modules. Using single-nucleus transcriptomics, we further revealed that these modules are enriched for specific classes of both excitatory and inhibitory neurons, and immunohistochemistry confirmed expression of highly correlated genes. This unprecedented dataset of patient-specific brain oscillations coupled to genomics unlocks new insights into the genetic mechanisms that support memory encoding.

 

Dr Elvira Perez Vallejos, Architecture of human brain networks

Virtual Brain meeting with UK DRI

6th May 4pm - 5pm

Dr Elvira Perez Vallejos

Indiana University

"The architecture of human brain networks"

Dr Stefan Schoenfelder, Long-range enhancer-promoter

Neurogenomics seminar

20 April 15:30-16:30

Dr Stefan Schoenfelder

Babraham Institute

"Long-range enhancer-promoter contacts in developmental gene expression control"

Enhancers are gene regulatory elements dispersed throughout the non-coding genome that control spatiotemporal gene expression programmes during mammalian development. Enhancers can be located at considerable genomic distances to the target genes they regulate (in some cases hundreds of kilobases) and they can skip over more proximally located genes to regulate their target genes through direct physical contacts. This is crucial for normal development, as is evident from the finding that aberrant enhancer-promoter contacts can lead to developmental disorders. We have developed Promoter Capture Hi-C (PCHi-C), a method to map enhancer-promoter contacts genome-wide at high resolution. We have used PCHi-C to interrogate the dynamics of enhancer-promoter contacts during cellular differentiation and in response to developmental stimuli, with a focus on mouse and human pluripotent stem cell models. A current focus of our research is to understand how genetic variants in enhancers impact the gene regulatory landscape and how they shape inter-individual differences in human induced pluripotent stem cell differentiation potential. I will conclude by presenting a model to explain how enhancers may find their target genes in the three-dimensional space of the nucleus.

Dr Walter Karlen, Closing loops with digital health systems

Virtual Brain meeting with UK DRI

8th April 4pm - 5pm

Dr Walter Karlen

ETH Zurich

"Closing loops with digital health systems"

Dr Jeremy Schwartzentruber, Alzheimer’s disease risk genes

Neurogenomics Seminar

23 March 4pm-5pm

Dr Jeremy Schwartzentruber 

Open Targets 

"Genome-wide meta-analysis, fine-mapping and integrative prioritization implicate new Alzheimer’s disease risk genes"

Genome-wide association studies have discovered numerous genomic loci associated with Alzheimer’s disease (AD); yet the causal genes and variants are incompletely identified. We performed an updated genome-wide AD meta-analysis, which identified 37 risk loci, including new associations near CCDC6TSPAN14NCK2 and SPRED2. Using three SNP-level fine-mapping methods, we identified 21 SNPs with >50% probability each of being causally involved in AD risk and others strongly suggested by functional annotation. We followed this with colocalization analyses across 109 gene expression quantitative trait loci datasets and prioritization of genes by using protein interaction networks and tissue-specific expression. Combining this information into a quantitative score, we found that evidence converged on likely causal genes, including the above four genes, and those at previously discovered AD loci, including BIN1APH1BPTK2BPILRA and CASS4.

 

Dr Francois Guillemot, Coming of age of neural stem cells

Division of Neuroscience and UK DRI

17th March 4pm - 5pm

Dr Francois Guillemot

The Francis Crick Institute

“The coming of age of neural stem cells”.

Dr Hyejung Won, 3D maps of chromatin contacts

Neurogenomics seminar

Tuesday 23rd February 10-11am

"3D maps of chromatin contacts unravel neurobiological mechanisms of brain disorders"

Genome-wide association studies (GWAS) have provided insights into the genetic etiology of neurological and substance use disorders. However, extracting biological mechanisms from GWAS data is a challenge, because the majority of common risk variants reside in noncoding regions of the genome. These non-coding variants often regulate distal genes via forming long-range chromatin interaction. In this talk, I will outline how high-resolution 3D maps of chromatin contacts in the human brain permit large-scale annotation of non-coding variants. I will further discuss how 3D chromatin contacts differ across different cell types and neuronal subtypes in the brain. Then I will introduce a novel platform that my lab has developed, Hi-C-coupled MAGMA (H-MAGMA), that annotates GWAS by incorporating chromatin interaction profiles from human brain tissue. By building H-MAGMA upon cell-type specific Hi-C data, the framework identifies neurobiologically relevant target genes for brain disorders in a cell-type specific manner. We applied H-MAGMA to neurological and substance use disorders to interrogate biological pathways, neural circuitry, and cell types implicated for each disorder.

Dr Song Chen, Mapping cellular diversity in the human brain

Neurogenomics Seminar

Tuesday 9th February 3-4pm

Dr Song Chen

Wellcome Sanger Institute

"Mapping cellular diversity in the human brain by high-throughput single-nucleus transcriptome and chromatin accessibility sequencing"

RNA sequencing of single cells reveals the transcriptional state of individual cells, whereas chromatin accessibility sequencing uncovers the upstream transcriptional regulatory landscape. To investigate the cellular diversity within the human adult brain, we have built high throughput single-nucleus sequencing platforms that allow the construction of cellular transcriptional states and epigenetic states separately. To enable the direct matching of transcriptional regulation to its output at a single cell level, we have also developed dual-omics sequencing methods called SNARE-seq. This novel joint-profiling method provides unprecedented biological insights into the cell-state transition in the brain, and represents a great single-cell multi-omics tool for the construction of the cell atlas of the human brain and other organs. 

Zoom meeting ID      929 6785 3304
Password                     865253
https://zoom.us/j/92967853304?pwd=MXJOU09hbVU0TTV6NWszTnFUWTJZZz09  

 

Professor Selina Wray, Human stem cell models of Alzheimer's Disease

UK DRI Virtual Brain Meeting

Thursday 4th February 4-5pm

Professor Selina Wray

University College London

"Human stem cell models of Alzheimer's Disease"

Dr Mahmoudreza Rafiee, Chromatin-RNA-binding proteins

Brain sciences seminar

27th January 4-5pm

Dr Mahmoudreza Rafiee

Marie Curie & EMBO postdoc fellow at The Francis Crick Institute London

Exploring chromatin-RNA-binding proteinsin pluripotency and ALS model system” 

Chromatin functions are regulated by organizing the assembly of specialized machinery at specific loci. Phase separation is thought to play a key role in organizing chromatin, protein- protein and protein-RNA interactions. In particular, RNA-binding proteins (RBPs) contribute to the phase separations by their intrinsically disordered regions (IDRs). Although DNA-protein and RNA-protein interactions have been studied extensively, reliable quantification of chromatin- associated RBPs is necessary to understand how they are involved in transcriptional regulations and chromatin activities. Here, we present SPACE (Silica Particle Assisted Chromatin Enrichment), a sensitive yet stringent chromatin-purification method that allows identification of chromatin-binding sites of the RBPs. Our results in mouse embryonic stem cells reveal more than 600 RBPs that bind to chromatin most frequently via their IDRs. Furthermore, we assessed the capacity of SPACE to be used with limited input material, which demonstrated reproducible enrichment of 1700 proteins from 100,000 cells using a single injection to mass spectrometer. Additionally, we applied SPACE to neural precursors containing VCP mutations. As a result, we discovered reduced chromatin-binding of mutant VCP, which itself causes reduced chromatin- binding of other DNA-damage components such as P53BP1. Thus motor neurons with mutant VCP are more vulnerable to DNA damage. These results demonstrate that high sensitivity and specificity of SPACE can lead to new insights into disease-causing mechanisms, indicating that SPACE will be particularly valuable for studies that are limited by input material. 

Professor Steven Brown, Cellular and Circuit Mechanisms

Neuroscience seminar

20th January 4-5pm

Professor Steven Brown

University of Zurich- Chronobiology and Sleep Research Group, Institute of Pharmacology and Toxicology 

“Cellular and Circuit Mechanisms Driving Circadian Control of Sleep”

What are the biological mechanisms that make us prefer to sleep during the night, and other animals during the day? In part, this is a question of brain circuitry, but it is also influenced by molecular clocks within our cells. In this talk, we’ll look at both aspects of these mechanisms, and the physiology that they control. 

Brian Schilder- Profile epigenetic landscapes

Neurogenomics seminar

15th December 4-5pm

Brian Schilder

UK DRI at Imperial College London

 “Profile epigenetic landscapes to better detect, classify, and understand human prion diseases”

Fine-mapping aims to distinguish causal genetic variants from their close correlates within phenotype-associated loci discovered through Genome Wide Association Studies (GWAS). However, different fine-mapping tools can lead to different but partially overlapping credible sets due to varying statistical assumptions and input data (e.g. functional annotations). We therefore developed echolocatoR to facilitate running a suite of complementary fine-mapping methods and extract high-confidence consensus SNPs nominated in the credible sets of multiple tools. This streamlined approach has allowed us to fine-map nearly all known loci across 12 neurological disease GWAS, including Parkinson’s Disease, Alzheimer’s disease, schizophrenia, and multiple sclerosis. All results will be made publicly accessible through the Fine-mapping Results Portal(https://rajlab.shinyapps.io/Fine_Mapping_Shiny).

Dr Sam Cooke, Dissecting Neocortical Circuits for the Detection of Novelty

Brain sciences seminar

9th December 4-5pm

Dr Sam Cooke

Kings College London

“Dissecting Neocortical Circuits that Enable the Detection of Novelty”

Habituation describes a range of learning processes that adaptively filter out innocuous stimuli, enabling organisms to devote themselves to important elements of the environment. Disruption to these processes divides attention and energy expenditure and therefore has devastating knock-on consequences for higher order cognition. I will describe our work to identify some of the mechanisms and circuitry that mediate this foundational process, starting with our observations that habituation across different timescales is accomplished by various forms of plasticity manifest in thalamo-recipient layer 4 of primary sensory cortex.

Dr Alexi Nott, Gene regulation in health and disease

UK DRI Seminar

25th November 4-5pm

Dr Alexi Nott

UK DRI Imperial 

“Epigenome of the brain: gene regulation in health and disease”

Alexi completed his PhD at University College London investigating the function of epigenetic regulators during brain development. During his postdoctoral fellowship at MIT he investigated the role of epigenetics in postnatal development and autism-related behaviors. His research at the University of California, San Diego examined epigenetic mechanisms underlying age-related brain disorders and he identified microglia as associated with the genetic risk of Alzheimer’s disease.
His research utilizes nuclei isolation methods and genome-wide sequencing approaches to examine the epigenome of brain cell types using patient-derived archived tissue. Functional interrogation of disease-associated gene regulatory regions will employ CRIPSR DNA-editing technology of pluripotent stem cells derived into brain cell types. Using a combination of these approaches, Alexi will examine the epigenome of the human brain to understand how genetic variation contributes to age-related brain disorders.

Dr Emmanuelle Viré, Profile epigenetic landscapes to understand human prion diseases

Neurogenomics seminar

24th November 4-5pm

Dr Emmanuelle Viré

UCL Institute of Prion Diseases

“Profile epigenetic landscapes to better detect, classify, and understand human prion diseases”

Prions are proteins that can adopt multiple conformations, at least one of which can self-template and mediate protein- based inheritance. Prions represent a paradigm in biomedicine, the so-called prion-like behaviour, where misfolded proteins (also called toxic conformation) are typically insoluble and tend to form aggregates. The consequences of misfolding events are univocally devastating and cause specific diseases. Although human prion diseases are rare, they are always fatal, and usually rapidly progressive neurodegenerative disorders. Because prions are infectious particles, prion diseases are transmissible. Although recent studies have implicated epigenetic variation in common neurodegenerative disorders, no study has yet explored their role in human prion diseases. 

I will describe our work, using blood and brain samples taken from patients, and profiling epigenetic and genetic landscapes. In particular, we explore DNA methylation, gene expression, non-coding RNAs and genetic profiles in samples from patients with the most common human prion disease, sporadic Creutzfeldt-Jakob disease (sCJD). Our approach aims at improving diagnosis, disease classification, providing targets for therapeutic interventions (new or repurposed drugs), help predict if treatment will work (or resistance will occur), and refine predictions on disease duration. We integrate our results with hits from genome-wide associations studies performed in the lab; clinical features; and compare them to similar studies in other misfolded protein disorders. I will present our most recent findings and discuss their relevance to disease management.

 

 

 

 

 

 

2019/20 Seminars

Dr Can Zhang, Pathogenic Mechanisms and Therapeutic Intervention

Alzheimer’s Disease – Pathogenic Mechanisms and Therapeutic Intervention

Dr Can Zhang
Massachusetts General Hospital & Harvard Medical School

Biography

Dr. Can (Martin) Zhang is an Assistant Professor of Neurology at the Massachusetts General Hospital (MGH) and the Harvard Medical School (HMS). Dr. Zhang received his MD and Master’s degree at the Weifang Medical College, China and then his PhD at Drexel Univ., PA, followed by a post-doctoral fellowship at MGH, before he became an Assistant Professor of Neurology at MGH and HMS.

Dr. Zhang’s research has been focused on abeta-related molecular mechanisms and compounds in Alzheimer’s disease (AD), particularly those with potentials for a better understanding and intervention of AD. He has studied AD-related genes and compounds that modulate abeta generation, including UBQLN1, ATXN1, curcumin, gamma-secretase modulators (GSMs) and elastin-like proteins; and recently molecules that change abeta clearance mediated by microglia, including cromolyn and an herbal remedy HLXL. These preclinical findings have not only provided mechanistic evaluation of drugs currently under clinical trial investigation for AD, e.g. cromolyn, but also promoted potential trials in AD for molecules, including GSMs and HLXL. Dr. Zhang has also studied aging-related biomarkers underlying AD, including gamma-secretase, RIPK1 and Sirt1, and is co-inventing new molecular probes for visualizing these proteins in the brain.

Abstract


Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the primary cause of dementia with no cure. Although the pathogenesis of AD has not been completely elucidated, evidence suggests that it is centered on cerebral accumulation of the small peptide, β-amyloid (Aβ), a proteolytic cleavage product of amyloid-β precursor protein (APP) by β- and γ-secretase. Characterization of molecular mechanisms that change Aβ levels and APP processing should new provide insights and elucidate the pathogenesis of AD; and development of interventions that reduce Aβ levels may provide potential therapeutics for AD.


Host


Hosted by Dr Yu Ye (yu.ye1@imperial.ac.uk)



Date and time

Wednesday 5th August 2020
15:00-16:00

Location
Zoom online seminar

Dr Charles Breeze, Atlas and developmental dynamics of mouse DNase

Atlas and developmental dynamics of mouse DNase I hypersensitive sites


Dr Charles Breeze
National Cancer Institute, NIH

Abstract

Early mammalian development is orchestrated by genome-encoded regulatory elements populated by a changing complement of regulatory factors, creating a dynamic chromatin landscape. To define the spatiotemporal organization of regulatory DNA landscapes during mouse development and maturation, we generated nucleotide-resolution DNA accessibility maps from 15 tissues sampled at 9 intervals spanning post-conception day 9.5 through early adult, and integrated these with 41 adult-stage DNase-seq profiles to create a global atlas of mouse regulatory DNA. Collectively, we delineated >1.8 million DNase I hypersensitive sites (DHSs), with the vast majority displaying temporal and tissue-selective patterning. Here we show that tissue regulatory DNA compartments show sharp embryonic-to-fetal transitions characterized by wholesale turnover of DHSs and progressive domination by a diminishing number of transcription factors. We show further that aligning mouse and human fetal development on a regulatory axis exposes disease-associated variation enriched in early intervals lacking human samples. Our results provide an expansive new resource for decoding mammalian developmental regulatory programs.

Host

Hosted by Dr Sarah Marzi (s.marzi@imperial.ac.uk)

Date and time

Tuesay 28th June
12:00-13:00

Location

Zoom online seminar


Dr Lars Velten, Targeted Perturb-seq enables genome-scale genetic screens

Targeted Perturb-seq enables genome-scale genetic screens in single cells


Dr Lars Velten
Centre for Genomic Regulation

Abstract

The transcriptome contains rich information on molecular, cellular and organismal phenotypes. However, experimental and statistical limitations constrain sensitivity and throughput of genetic screening with single-cell transcriptomics readout. To overcome these limitations, we introduce targeted Perturb-seq (TAP-seq), a sensitive, inexpensive and platform independent method focusing single-cell RNA-seq coverage on genes of interest, thereby increasing the sensitivity and scale of genetic screens by orders of magnitude. TAP-seq permits routine analysis of thousands of CRISPR-mediated perturbations within a single experiment, detects weak effects and lowly expressed genes, and decreases sequencing requirements by up to 50-fold. We apply TAP-seq to generate perturbation-based enhancer–target gene maps for 1,778 enhancers within 2.5% of the human genome. We thereby show that enhancer– target association is jointly determined by three-dimensional contact frequency and epigenetic states, allowing accurate prediction of enhancer targets throughout the genome. In addition, we demonstrate that TAP-seq can identify cell subtypes with only 100 sequencing reads per cell.

Host

Hosted by Dr Sarah Marzi (s.marzi@imperial.ac.uk)

Date and time Location

Wednesday 24th June
12:00-13:00


Location


Zoom online seminar

 

Dr Nael Nadif Kasri, Neurons-on-a-chip to model neurodevelopmental disorders

Neurons-on-a-chip to model neurodevelopmental disorders

Dr Nael Nadif Kasri
Radboud University Medical Center,
Donders Institute for Brain, Cognition and Behaviour

Biography

Nael Nadif Kasri, PhD., is associate professor at the Department of Human Genetics of Radboud University Medical Centre and is the head of the Molecular and Cellular Neurophysiology lab, consisting of two technicians, 9 PhD students and 3 postdocs. He is a neurobiologist who has extensive experience with the molecular mechanisms underlying synaptic plasticity, including imaging and electrophysiological methods in cellular and animal models. Since the start of his postdoctoral studies he has been interested in understanding the molecular mechanisms of neurodevelopmental disorders. In his postdoc he mainly focused on understanding the function of Intellectual disability (ID) genes related to the RhoGTPase pathway. In 2011 he joined the Human Genetics department (Nijmegen, the Netherlands) where he started several collaborations to understand the synaptic basis of ID. As such he has focused his research on several syndromes that were initially discovered in Nijmegen, being Kleefstra syndrome and Koolen-de Vries Syndrome. One of his recent contributions is the implementation of multi-electrode recordings in human induced pluripotent stem cells. This technique enables the stratification of patients who suffer from autism, epilepsy, which may lead to more specific therapies. Dr. Nael Nadif Kasri was awarded with a Human Frontiers fellowship at Cold Spring Harbor Laboratories (USA), where he performed his second postdoctoral study. Since 2011 he has his own research group at the Radboudumc, and became part of the Donders Institute in Nijmegen, the Netherlands. There he was granted a prestigious Hypatia fellowship, a Marie Curie Career Integration Grant, NIH DECODE grant and more recently a SFARI pilot grant.

Abstract


Great progress has been made over recent years towards the identification of genes linked to neurodevelopmental disorders (NDDs), resulting in hundreds of candidate genes. A remaining challenge, however, is to connect the genetic causes of NDDs to processes that establish and/or modify neuronal circuit function. The recent developments in induced pluripotent stem cells (iPSCs) have provided us with the ability to model patient-specific neuronal networks. In this talk I will discuss our strategy to link genetic deficits observed in patients with neuronal network measurements. We combine iPSC-derived neurons (excitatory and inhibitory) with micro-electrode arrays and transcriptomics analysis to unravel the pathomechanism underlying specific syndromes. I will discuss three well-described NDDs caused by mutations in different histone modifiers, respectively in EHMT1, KANSL1 and KMT2D. In general, our data indicate that neuronal network measurement of iPSC-derived neurons on MEAs is a robust and sensitive method to perform genotype-phenotype analyses for NDDs and can be a powerful platform for drug screening assays.


Date and time

Wednesday 8th July 2020
14:00-15:00

Location

Zoom online seminar

Anna Cuomo, Population-scale single-cell RNA-seq profiling

Population-scale single-cell RNA-seq profiling across dopaminergic neuron differentiation

 

Anna Cuomo

EMBL-EBI

Abstract

Common genetic variants can have profound effects on cellular function, but studying these effects in primary human tissue samples and during development is challenging. Human induced pluripotent stem cell (iPSC) technology holds great promise for assessing these effects across different differentiation contexts. Here, we use an efficient pooling strategy to differentiate 215 iPS cell lines towards a midbrain neural fate, including dopaminergic neurons, and profile over 1 million cells sampled across three differentiation timepoints using single cell RNA sequencing. We find that the proportion of neuronal cells produced by each cell line is highly reproducible over different experimental batches, and identify robust molecular markers in pluripotent cells that predict line-to-line differences in cell fate. We identify expression quantitative trait loci (eQTL) that manifest at different stages of neuronal development, and in response to oxidative stress, by exposing cells to rotenone. We find over one thousand eQTL that colocalise with a known risk locus for a neurological trait, nearly half of which are not found in GTEx. Our study illustrates how coupling single cell transcriptomics with long-term iPSC differentiation can profile mechanistic effects of human trait-associated genetic variants in otherwise inaccessible cell states.

Host

Hosted by Dr Sarah Marzi (s.marzi@imperial.ac.uk)

Date and time

Tuesday 7th July
15:00-16:00

Location

Zoom online seminar

Prof Jonathan Mill, (Epi)genomic trajectories to neuropsychiatric and neurodegenerative disease

(Epi)genomic trajectories to neuropsychiatric and neurodegenerative disease

Prof Jonanthan Mill

Professor of Epigenomics
University of Exeter Medical School

Biography

Jonathan Mill is Professor of Epigenomics at the University of Exeter Medical School. He graduated with a degree in Human Sciences from Oxford University, where he took a particular interest in cannibalism, before undertaking his PhD in Psychiatric Genetics at the Institute of Psychiatry, King’s College London. After spending three years as a Canadian Institutes of Health Research (CIHR) postdoctoral fellow at the University of Toronto, he returned to the Institute of Psychiatry to establish the Psychiatric Epigenetics group in the MRC Social, Genetic and Developmental Psychiatry Centre. He joined the University of Exeter Medical School in 2012 where he heads the Complex Disease Epigenomics Group. Jonathan’s group studies the role of epigenetic processes in complex disease, with a particular emphasis on neurodegenerative and neuropsychiatric phenotypes. Current areas of research include: 1) regulatory genomic profiling in post-mortem brain tissue; 2) investigating the role of epigenetic variation in mediating the onset of neuropathology in cellular/rodent models; 3) describing dynamic genomic processes in human brain development and aging; and 4) exploring interactions between the epigenome, environment and DNA sequence variation, with the aim of undertaking an integrated genetic-epigenetic approach to disease.

Abstract


The research in my group is focused on understanding both the ‘causes’ and ‘consequences’ of genomic variation in the brain, and the role this plays in neuropsychiatric and neurodegenerative disease. Despite major advances in understanding the risk factors (both genetic and environmental) for these diseases, the mechanisms involved in the onset and progression of pathology are not fully understood and long-term treatments to reverse cellular disease processes in the brain remain elusive. Although genetic studies have been highly successful in identifying variants associated with brain disorders, there remains uncertainty about the specific causal genes involved and how their function is dysregulated during the progression of neuropathology. Increased understanding about the functional complexity of the genome has led to recognition about the role of non-coding regulatory variation in health and disease. Our work aims to characterise the regulatory regions, epigenetic modifications and transcriptional patterns defining the different brain regions and cell-types in the human central nervous system, and assess their role in neurodevelopment, ageing and disease. In this talk I will present on-going work from my group aimed at identifying regulatory genomic variation associated with a diverse range of brain phenotypes. I will describe the dynamic nature of DNA modifications across human brain development and ageing and describe the impact of genetic variation on the epigenome during the life-course. Novel tools mean that it is now feasible to examine epigenetic variation across the genome in large numbers of samples, and I will give an overview of our recent epigenome-wide association studies (EWAS) of schizophrenia and dementia. Finally, I will outline some of the issues related to epigenetic epidemiological studies of neuropsychiatric disease and explore the feasibility of identifying peripheral biomarkers of disease phenotypes manifest in inaccessible tissues such as the brain.

Host

Hosted by Dr Sarah Marzi (s.marzi@imperial.ac.uk)

Date and time

Wednesday 24th June
12:00-13:00

Location

Zoom online seminar

Dr Vikram Agarwal, Predicting mRNA Abundance

Predicting mRNA Abundance Directly from Genomic Sequence Using Deep Convolutional Neural Networks

Dr Vikram Agarwal 

Calico Life Sciences

 Abstract

Algorithms that accurately predict gene structure from primary sequence alone were transformative for annotating the human genome. Can we also predict the expression levels of genes based solely on genome sequence? Here, we sought to apply deep convolutional neural networks toward that goal. Surprisingly, a model that includes only promoter sequences and features associated with mRNA stability explains 59% and 71% of variation in steady-state mRNA levels in human and mouse, respectively. This model, termed Xpresso, more than doubles the accuracy of alternative sequence-based models and isolates rules as predictive as models relying on chromatic immunoprecipitation sequencing (ChIP-seq) data. Xpresso recapitulates genome-wide patterns of transcriptional activity, and its residuals can be used to quantify the influence of enhancers, heterochromatic domains, and microRNAs. Model interpretation reveals that promoter-proximal CpG dinucleotides strongly predict transcriptional activity. Looking forward, we propose cell-type-specific gene-expression predictions based solely on primary sequences as a grand challenge for the field.

 

Host

Hosted by Dr Sarah Marzi (s.marzi@imperial.ac.uk)

Date & Time
Tuesday 23 June
17:00-18:00

Location

Zoom Online Seminar

 

Dr Diego Villar Lozano, Enhancer Evolution across 20 Mammalian Species

Enhancer Evolution across 20 Mammalian Species

 

Dr Diego Villar Lozano

Abstract

The mammalian radiation has corresponded with rapid changes in noncoding regions of the genome, but we lack a comprehensive understading of regulatory evolution in mammals. Here, we track the evolution of promoters and enhancers active in liver across 20 mammalian species from six diverse orders by profiling genomic enrichment of H3K27 acetylation and H3K4 trimethylation. We report that rapid evolution of enhancers is a universal feature of mammalian genomes. Most of the recently evolved enhancers arise from ancestral DNA exaption, rather than lineage-specific expansions of repeat elements. In contrast, almost all liver promoters are partially or fully conserved across these species. Our data further reveal that recently evolved enhancers can be associated with genes under positive selection, demonstrating the power of this approach for annottaing regulatory adaptations in genomic sequences. These results provide important insight into the functional genetics underpinning mammalian regulatory evolution.

Date and time

Tuesday 2nd June 2020
15:00-16:00

Location

Zoom Online Seminar

Dr Javier Alegre Abarrategui, Early aggregation in neurodegeneration

 
Visualisation in situ of early aggregation in neurodegeneration

 DrJavierAlegre Abarrategui

Dr Javier Alegre Abarrategui

Clinical Senior Lecturer in Neuropathology
Imperial College London

Biography

Dr Javier Alegre-Abarrategui is a Clinical Senior Lecturer at Imperial in Neuropathology at the Neurodegeneration and Neuroinflammation Centre, and Honorary Consultant Neuropathologist at Charing Cross Hospital. He was previously based in Oxford at the Department of Neuropathology and the Department of Physiology, Anatomy and Genetics. Javier’s research focused on genetically-defined forms of PD, the use of human genomic constructs for animal and in vitro functional modelling and autophagy. More recently he has pioneered the development of novel tools to detect in situ early protein aggregates such as alpha-synuclein oligomers in human brain and has started to apply these tools to the dissection of the initial pathogenic processes in PD and Alzheimer’s disease.

Abstract

Neurodegenerative diseases such as Alzheimer’s or Parkinson’s disease are characterised by the aggregation and accumulation in the brain of certain proteins, tau and beta-amyloid in the former, alpha-synuclein in the latter. These proteins are physiologically widely expressed in the brain. In order to visualise pathologically aggregated protein over the background of physiological protein in brain tissue, several strategies are used, such as the use of antibodies specific for posttranslational modifications (e.g. phosphorylation) associated with the abnormal protein. We have developed a strategy based on proximity ligation assays that utilises the basic event of protein self-interaction to visualise aggregated protein but not monomeric physiological protein. Our assays for alpha-synuclein and tau are offering us a previously unrecognised window into earlier aggregation pathology, which could lead to a better understanding of the cellular processes driving disease. 

Date and time

Wednesday 29th March 2020
12:15-13:15

Location

Zoom Online Seminar

Prof Peter Giese, Generation of 2-input synapses

A novel memory mechanism: Generation of 2-input synapses?

Peter GieseProf Peter Giese
Chair of Neuroscience of Mental Health
King's College London

Biography
Karl Peter Giese is Professor of Neurobiology of Mental Health at King's College London. He investigates memory mechanisms in health and disease, using mouse models. He has published more than 100 research articles and his current H-index is 51.

Abstract
A small fraction of the synapses in the hippocampus have two inputs. The role of these 2-input synapses is not well understood, but recently we obtained evidence that generation of these atypical synapses can enable memory formation when long-term potentiation (LTP) is impaired. First, we showed that in an LTP-deficient mouse model hippocampal memory can be formed and correlates with generation of 2-input synapses. Next, we found that 2-input synapses increase with ageing in the hippocampus and appear to enable memory formation, as LTP induction is impaired.  Finally, our findings suggest that memories based on 2-input synapses are not as flexible as memories involving LTP.

Host
Hosted by Dr Sam Barnes (Samuel.Barnes@imperial.ac.uk
Contact Dr Jennifer Podesta (j.podesta@imperial.ac.uk) to arrange to meet with the speaker

Date and time
Monday 16 December 2019
13.00-14.00

Location
E519 Burlington Danes Building, Hammersmith Campus

Dr Mikhail Spivakov, Dissecting the logic of remote gene control

Dissecting the logic of remote gene control

Mikhail SpivakovDr Mikhail Spivakov
MRC London Institute of Medical Sciences
Imperial College London 

We are interested in how genomic and epigenetic information is integrated with extrinsic signals to promote concerted changes in gene expression.

Abstract
Our lab combines experimental and computational approaches to understand the regulation and function of gene enhancers. Metazoan gene regulation relies on joint activity of multitudes of enhancers, many of which localise large distances away from their target genes. Enhancers are highly enriched for disease-associated variants, and also underpin some Mendelian developmental disorders, highlighting their importance in gene control. I will present our recent work including the development of the methodology for detecting enhancer-promoter interactions at high confidence, dissecting the mechanisms that facilitate these interactions and leveraging them for interpreting disease-associated variants.

Hosts
Hosted by Dr Nathan Skene and Dr Sarah Marzi

Date and time
Monday 09 December 2019
14.00-15.00

Location
E519 Burlington Danes Building, Hammersmith Campus

Dr Jean-Michel Fustin, The methyl cycle in health and disease

The methyl cycle in health and disease
Monday 16th September 2019
14.00-15.00
E519 Burlington Danes Building
Hammersmith Campus

Fustin

 

After completing his PhD in seasonal rhythms at the University of Aberdeen (United Kingdom), Dr Fustin came to Japan in 2008 as a postdoctoral fellow, to work with Prof. Okamura on the neurobiology of circadian rhythms at the Department of Systems Biology in Kyoto University. There, he developed his own interests in the link between the circadian clock and the metabolism of methyl groups. These studies led to the discovery that the N6-methylation of adenosine nucleotides within the mRNA sequence was a circadian pacemaker. In 2014, he became Adjunct Lecturer, then Associate Professor in 2018. He was the first European to obtain a tenured faculty position at the Graduate School of Pharmaceutical Sciences of Kyoto University, where he founded his Laboratory of Molecular Metabology in 2019. His investigations on RNA methylation led to the characterization of a novel alternatively-spliced Casein Kinase 1 Delta isoform, functionally distinct from the canonical one and expressed at higher levels in specific peripheral tissues. His laboratory now focuses on the physiological functions of mRNA methylation and the pathological consequences of RNA methylation deficiency in adult organisms. In 2019, he was awarded a UKRI Future Leaders Fellowship and will relocate to the University of Manchester in early 2020.

 

Dr Raffaella Nativio, The epigenetic landscape of healthy aging

The epigenetic landscape of healthy aging and Alzheimer's disease

Dr Raffaella NativioDr Raffaella Nativio
Research Associate in Epigenetics
University of Pennsylvania

 

Abstract
Aging is the top risk factor for Alzheimer's disease (AD),although the underlying mechanisms remain unclear. The chromatin state, in particular through the mark H4K16ac, has been implicated in aging and thus may play a pivotal role in age-associated neurodegeneration. Here we compare the genome-wide enrichment of H4K16ac in the lateral temporal lobe of AD individuals against both younger and elderly cognitively normal controls. We find that while normal aging leads to H4K16ac enrichment, AD entails dramatic losses of H4K16ac in the proximity of genes linked to aging and AD. Our analysis highlights the presence of three classes of AD-related changes having distinctive functional roles. Furthermore, we discover an association between the genomic locations of significant H4K16ac changes with genetic variants (SNPs) identified in prior AD genome-wide association studies (GWAS) and with expression quantitative trait loci (eQTLs). Our results establish the basis for an epigenetic link between aging and AD

Host
Hosted by Professor Paul M Matthews (p.matthews@imperial.ac.uk)
Contact Dr Jennifer Podesta (j.podesta@imperial.ac.uk) to arrange to meet with the speaker.

Date and time 
Monday 29 July 2019
16:00 - 17:00

Location
E519 Burlington Danes, Hammersmith Campus 

 

Dr Silvia Bolognin, Stem cell-derived 3D in vitro cultures


Stem cell-derived 3D in vitro cultures as a relevant model for Parkinson’s disease

Dr Silvia BologninDr Silvia Bolognin
Luxembourg Centre for Systems Biomedicine (LCSB)
University of Luxembourg



Biography
Dr. Silvia Bolognin is a research associate at the University of Luxembourg. She graduated in Pharmaceutical Chemistry and Technology and she received her Ph.D. in Tissue and Grafting Engineering at the University of Padua, Italy. She was a post-doc fellow at the Institute for Basic Research in Developmental Disabilities in Staten Island, NY in the lab of prof. Khalid Iqbal and at the University of Verona, Italy. She was also a co-founder and acted as CTO of a spin-off company from the University of Luxembourg. Dr. Bolognin has focused on the mechanisms that regulate abnormal protein alteration in Alzheimer´s and Parkinson´s disease and the use of stem cell technology for disease modelling.

Abstract
The identification of promising drug candidates against Parkinson’s disease (PD) is hampered by the lack of sufficiently representative in vitro models. Human induced pluripotent stem cells (iPSCs) represent a promising tool to fill this gap. We optimized the cultivation of PD patient-specific neurons, derived from patients carrying the LRRK2-G2019S mutation, in 3D microfluidics. 3D conditions elicited an intrinsic time dependent dopaminergic degeneration due to LRRK2-G2019S, which was not observed in standard 2D conditions. This was preceded by an altered mitochondrial morphology, and increased cell death in LRRK2-G2019S neurons compared to isogenic lines without using stressor agents. We further increased the complexity of the models by generating midbrain organoids. In LRRK2-G2019S midbrain organoids, a decreased expression of astrocytes was observed after 35 days of differentiation. This was accompanied by an altered transcriptomic profile as shown by single-cell RNA sequencing. Interestingly, the defective astrocyte differentiation and the dopaminergic degeneration contributed to the acquisition of a senescent phenotype in organoids carrying the LRRK2-G2019S mutation. This data supports the use of advanced in vitro models to recapitulate key pathological hallmarks of this neurodegenerative disorder.

Host
Hosted by Professor Paul M Matthews (p.matthews@imperial.ac.uk)
Contact Dr Jennifer Podesta (j.podesta@imperial.ac.uk) to arrange to meet with the speaker.

Date and time 
Wednesday 24 July 2019
15:00 - 16:00

Location
E519 Burlington Danes, Hammersmith Campus 

 

 

Dr Yu Ye, Reversing protein aggregation in dementia


Maintaining cell homeostasis by proteasome re-organisation – reversing protein aggregation in dementia


Dr Yu YeDr Yu Ye
Sir Henry Wellcome Research Fellow in Biotechnology
University of Cambridge and Harvard University



Biography
Yu Ye completed his PhD at the MRC-LMB, studying how deubiquitinating enzymes of the ubiquitin-proteasome system (UPS) interacted with distinct ubiquitin signals. During this time, he uncovered a novel mechanism of regulating deubiquitinase activity through the conformation of ubiquitin chains. Several of these deubiquitinases have since been shown to regulate cell stress responses implicated in neurodegenerative disorders. Awarded with a Sir Henry Wellcome Fellowship for his postdoctoral research, he initiated and built up a collaboration between Harvard and Cambridge to develop his own research direction, focusing on reversing protein aggregation with the UPS. He conceptualised and directed research in this novel area, for which he also established a dedicated research infrastructure. This resulted in several senior-author studies describing how proteasomes actively restricted aggregate size in vitro and how proteasomes re-organised to target aggregates in cells. He is now excited to expand this novel area of research into understanding the role of proteasome function in dementia.

Abstract
Aggregation of misfolded proteins is a pathological process implicated in neurodegenerative disorders and dementia. While much research has focused on how aggregates are assembled, the reverse process of aggregate removal is not well-studied. Reducing cell stress by limiting toxic protein aggregates is an important area of research, opening up novel potential routes of therapeutic intervention. Using state-of-the-art super-resolution and light-sheet microscopy and cell biology approaches, I have developed a unique research direction to investigate how proteasomes maintain cell homeostasis by targeting aggregates at distinct localisations. I also built up a dedicated research infrastructure and methodological approaches to study proteasomes and protein aggregates in cells. My in vitro results and studies in cells demonstrated that proteasomes restricted aggregate size and reorganised upon cell stress, assembling into foci around aggregates in a cytoskeleton-dependent manner. I will now to expand my research into characterising the mechanisms underlying proteasome response during aggregate entry into neurons, and during aggregate formation inside neurons over time. Uncovering processes involved in aggregate clearance and how proteasome malfunction is implicated in neuronal stress and degeneration will provide a better understanding of neurodegenerative disorders and ultimately establish approaches to restrict and reverse dementia.

Host
Hosted by Professor Paul M Matthews (p.matthews@imperial.ac.uk)
Contact Dr Jennifer Podesta (j.podesta@imperial.ac.uk) to arrange to meet with the speaker.

Date and time 
Friday 26 July 2019
11:30 - 12:30

Location
E519 Burlington Danes, Hammersmith Campus 

 

Dr Nathan Skene, Genetic identification of cell types


Genetic identification of cell types underlying brain disorders and cognitive traits

Dr Nathan SkeneDr Nathan Skene 
Edmond and Lily Safra-UK DRI Junior Research Fellow in Bioinformatics
Imperial College London


Biography
Nathan Skene did an undergraduate degree in Artificial Intelligence and Cybernetics at the University of Reading, followed by an MPhil in Computational Biology at Cambridge. His PhD was at the Sanger Institute working with Prof Seth Grant on the Genes2Cognition programme. During his PhD he worked on analysing the transcriptomic changes seen in a mice carrying a wide range of synaptic mutations. His interests lie in using human genetics to gain insight into the neurobiology of brain disorders and cognitive traits. He did his postdoc in the lab of Jens Hjerling-Leffler at the Karolinska Institutet, where he developed a series of method which made it possible to identify cell types underlying complex diseases using GWAS data. He recently moved to Imperial as an Edmund and Lily Safra Fellow.

Abstract
Using a cellular taxonomy of the brain from single-cell RNA sequencing we have evaluated whether disease associated genomic loci are linked to particular brain cell types. We find evidence that schizophrenia is best explained by independent associations with four cell types: medium spiny neurons, cortical neurogliaform cells, pyramidal neurons and glutamatergic cells of the superior colliculus. We find that other psychiatric and cognitive traits which show strong genetic correlations to schizophrenia due to shared cellular mechanisms. Depression and neuroticism are however found to have greater involvement of the dopaminergic and serotonergic cell types. Neurological disorders show clear differences with Alzheimers associated with microglia, Parkinsons with dopaminergic cells and oligodendrocytes, and Stroke with arterial smooth muscle cells. As no prior studies had implicated oligodendrocytes as being causally involved in Parkinsons, we further investigated cellular changes in post-mortem Parkinson’s brains: we found that changes in oligodendrocytes precedes dopaminergic neuron degeneration in the substantia nigra.

Host
Hosted by Professor Paul M Matthews (p.matthews@imperial.ac.uk)
Contact Dr Jennifer Podesta (j.podesta@imperial.ac.uk) to arrange to meet with the speaker.

Date and time 
Monday 22 July 2019
16:00 - 17:00

Location
E519 Burlington Danes, Hammersmith Campus 

 

Dr Sarah Marzi, Dysregulation of histone acetylation

 

Dysregulation of histone acetylation in Alzheimer’s disease

Dr Sarah MarziDr Sarah Marzi
Centre for Genomics and Child Health, Blizard Institute
Queen Mary University of London



Biography
Sarah Marzi studied mathematics and psychology at the University of Freiburg before completing a PhD in epigenetics at King’s College London.  Her research interests lie in epigenetics of human complex diseases, particularly those relating to brain and neuropsychiatric phenotypes, and she uses genome-wide genetic and epigenetic techniques as well as innovative bioinformatic and statistical approaches to investigate epigenetic dysregulation in disease. Sarah is currently a postdoctoral researcher in Vardhman Rakyan’s lab at Queen Mary University of London working on epigenetic responses to nutritional stressors and genetic variation in human ribosomal DNA.

Abstract
Recent studies have implicated a role for regulatory genomic variation in Alzheimer’s disease (AD) progression, finding widespread evidence for altered DNA methylation associated with neuropathology. To date, however, few studies have systematically examined other types of regulatory genomic modifications in AD. This talk will focus on results from a recent genome-wide study of lysine H3K27 acetylation (H3K27ac) – a robust marker of active enhancers and promoters – in entorhinal cortex samples from AD cases and matched controls (Marzi et al., 2018. Nat Neurosci). 

In addition to widespread acetylomic variation associated with AD neuropathology, we identified differentially acetylated peaks in the vicinity of genes implicated in both tau and amyloid neuropathologies, as well as in genomic regions containing variants associated with sporadic late-onset AD. Partitioned heritability analysis highlighted a significant enrichment of AD risk variants in entorhinal cortex H3K27ac peak regions and AD-associated variable H3K27ac was associated with transcriptional variation at proximal genes including CR1, GPR22, KMO, PIM3, PSEN1, and RGCC. This is the first study of variable H3K27ac yet undertaken for AD; in addition to identifying molecular pathways associated with AD neuropathology, it serves as a framework for quantitative genome-wide studies of this modification in complex disease. 

Host
Hosted by Professor Paul M Matthews (p.matthews@imperial.ac.uk)
Contact Dr Jennifer Podesta (j.podesta@imperial.ac.uk) to arrange to meet with the speaker.

Date and time 
Wednesday 17 July 2019
16:00 - 17:00

Location
E519 Burlington Danes, Hammersmith Campus 

2018/19 Seminars

Prof Valerie O'Donnell, Vascular inflammation and lipidomics of ApoE

Prof Valerie O'DonnellVascular inflammation and lipidomics of ApoE
Guest lecture - Tuesday 5 February 2019
Professor Valerie O’Donnell 
Director, Division of Infection and Immunity & Co-Director of Systems Immunity Research Institute, Cardiff University

 

Biography

Valerie O’Donnell is currently Director of Division of Infection and Immunity at Cardiff University, and Co-Director of Systems Immunity Research Institute which she co-founded in 2016 (£4.2M).  She is Strategic Management lead of the LIPID MAPS Gateway (www.lipidmaps.org) which is a Wellcome Trust funded bioresource, joint led with UCSD and Babraham, and with over 1M users annually.  She supervises an interdisciplinary group of scientists with biomedical, clinical and physical sciences backgrounds.  She is an ERC Advanced Investigator and lipid biochemist whose research is focused on using mass spectrometry for discovery and characterization of new lipid mediators of inflammation.  For the last 10 yrs she has studied how specialized lipids generated by circulating vascular cells regulate inflammation, wound healing and thrombosis.  She particularly focused on around 150 molecular species of lipids termed enzymatically-oxidized phospholipids (eoxPL) made by platelets, neutrophils, monocytes and eosinophils. They were discovered, characterized and chemically synthesized in her group, and then analyzed in vitro and in vivo in human clinical samples and mouse models, for their biological and pathophysiological actions.  In collaboration with Collins and Krönke, she showed that they are essential for normal blood clotting, and conversely are elevated in thrombotic disease (1-3). The detailed biochemical and biophysical mechanisms of action were elucidated.  Valerie also showed they regulate neutrophil antibacterial actions and transcriptional activation in monocytes. With Conrad, a key role for eoxPL in a cell death pathway, ferroptosis, was found (4). eoxPL are an essential part of the healthy innate immune system, however when inappropriately generated in the blood stream or in excess, they contribute directly to vascular inflammation.   

1.     Lauder, SN et al (2017) Networks of enzymatically oxidized membrane lipids support calcium - dependent coagulation factor binding to maintain hemostasis. Science Signaling Vol. 10, Issue 507, eaan2787, DOI: 10.1126/scisignal.aan2787

2.     Uderhardt et al (2017) Enzymatic lipid oxidation by eosinophils propagates coagulation, hemostasis and thrombotic disease  J Exp Med 214(7):2121-2138. doi: 10.1084/jem.20161070

3.     Slatter et al (2016) Mapping the human platelet lipidome reveals cytosolic phospholipase A2 as a regulator of mitochondrial bioenergetics during activation. Cell Metabolism 23, 930-934, with commentary by FitzGerald, GA, Human platelet lipidomics: variance, visualization, flux and fuel.  23, 757-759

4.     Friedmann Angeli et al (2014) Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nature Cell Biology (DOI: 10.1038/ncb3064) 16, 1180–1191 [IF 20.7]

Abstract

Enzymatically-oxidized phospholipids (eoxPL) are generated through regulated processes, by attaching eicosanoids or prostaglandins to phospholipids (PL) in immune cells, following acute agonist activation. These lipids comprise structurally diverse families of biomolecules, and it is becoming increasingly clear that they possess significant immunoregulatory roles in both health and disease. The idea that oxidized PL (oxPL) can form via enzymatic pathways and signal biologically in their own right has only recently been realized. eoxPL form through the co-ordinated actions of cellular lipoxygenases, cyclooxygenases, and Land’s cycle enzymes. They display emerging roles in cellular events that include ferroptosis, apoptosis and blood clotting, and diseases such as arthritis, diabetes and cardiovascular disease. In our lab, we used several mass spectrometry approaches (precursor scanning, untargeted) to map eoxPL in human blood cells, including platelets, neutrophils and monocytes, both in isolation and during formation of a static clot. Platelets generate over 100 molecular species on thrombin activation, and mice that lack the ability to generate these show a consumptive coagulopathy and are protected against atherosclerosis and aortic aneurysm. Our recent studies have characterised the biophysical mechanisms by which eoxPL promote blood clotting, and in this talk, our recent studies on their role(s) in vascular inflammation and hemostasis will be presented. We are currently extending our work to the characterisation of the role of these unique lipids in brain vascular health and disease, but this is very early stage so preliminary data on this will be presented.  

Host

Professor Paul Matthews (p.matthews@imperial.ac.uk)
Contact Dr Jennifer Podesta (UKDRI@Imperial.ac.uk) to arrange to meet with the speaker

Date and time

Tuesday 5 February 2019
12:30 - 13:30
Light lunch available from 12:00 in the Wolfson Cafe

Venue

Seminar rooms 4 and 5, Wolfson Education Centre, Hammersmith Campus

 

 

Dr Katie Lunnon, Epigenetics in AD

 Epigenetic mechanisms in Alzheimer’s disease

Katie LunnonGuest lecture - Wednesday 30 January 2019
Dr Katie Lunnon
Associate Professor in Epigenetics
University of Exeter Medical School

Biography

Katie is an Associate Professor in Epigenetics at the University of Exeter Medical School, with a particular interest in dementia. Her group published the first genome-wide, cross-tissue epigenome-wide association study (EWAS) in Alzheimer’s disease (AD) (Lunnon et al, Nat Neurosci-2014), which has been cited >200 times. This year her group published a follow up EWAS paper highlighting differential DNA methylation across an extended 48kb region in the HOXA3 gene in individuals with AD (Smith et al, Alzheimers Dement-2018). Katie currently leads a team of three postdoctoral researchers and five postgraduate students, who are utilising a range of cutting-edge methodologies to elucidate the role of epigenetic mechanisms in dementia. They are using sophisticated bioinformatics approaches to meta-analyse all available AD EWAS datasets and also perform integrative multi-omics analyses in well characterised cohorts to combine different levels of molecular information. They are also performing a range of wet lab molecular and cellular biology experiments, including epigenetic editing in induced pluripotent stem cells (iPSCs).

Katie was recently awarded the Alzheimer’s Research UK Young Investigator of the Year award in 2017 and an Alzheimer’s Society Dementia Research Leaders award in 2015 for academic achievements.  Katie is module lead for the final year double (30) credit module "Frontiers in Neuroscience" on the BSc Medical Sciences program, co-ordinator of the Alzheimer’s Research UK South West Network Centre and sits on the ARUK grant review board.

Host

Professor Paul Matthews (p.matthews@imperial.ac.uk)
Contact Dr Jennifer Podesta (UKDRI@Imperial.ac.uk) to arrange to meet with the speaker

Date and time

Wednesday 30 January 2019
12:30 - 13:30
Light lunch available from 12:00 in the Wolfson Cafe

Venue

Wolfson Education Centre
Hammersmith Campus

Directions to the Hammersmith Campus and campus map are available on the College 'visit Hammersmith' web page

Prof Giles Hardingham, Degeneration and resilience

Signaling pathways to degeneration and resilience in the CNS

Giles Hardingham

Guest lecture - 14 November
Professor Giles Hardingham
Associate Director, UK Dementia Research Institute at
The University of Edinburgh

 

Biography


Professor Giles Hardingham studied biochemistry at the University of Cambridge before completing a PhD at the MRC Laboratory of Molecular Biology. He established his laboratory at the University of Edinburgh in 2002 as a Royal Society University Research Fellow, moving onto a MRC Senior Non-Clinical Research Fellowship in 2010. He currently holds the City of Edinburgh Chair of Pharmacology and is an Associate Director of the UK DRI, leading the Edinburgh centre. 

Selected references


McKay S et al (2018) Cell Reports 
Hasel P et al (2017) Nature Communications
Hardingham GE et al (2018) Nature Reviews Neuroscience
Hardingham & Do (2016) Nature Reviews Neuroscience

Prof Michael Heneka, Alzheimer's disease and innate immunity

Does innate immunity contribute to Alzheimer's disease? 

Michael HenekaGuest lecture - 4 October
Professor Michael T Heneka
Department of Neurodegenerative Disease and Geriatric Psychiatry
University of Bonn
Bonn, Germany

Accumulation of neurotoxic amyloid-b peptides along with neurofibrillary tangle formation represent key pathological hallmarks in Alzheimer’s disease (AD). Despite the brain has been viewed as an immune privileged organ, increasing evidence from translational, genetic and pathological studies suggests that activation of distinct innate immune pathways represents a third important component, which, once initiated, actively contributes to disease progression and chronicity. Microglia play a pivotal role in this immune response and are activated by binding of aggregated proteins or aberrant nucleic acids to pattern recognition receptors. This immune activation leads to the release of inflammatory mediators but also distracts microglia cells from their physiological functions and tasks. NLRP3 inflammasome activation and release of ASC specks contribute to spreading of pathology and impairs microglia clearance mechanisms together contributing to neuronal degeneration and spatial memory deficits. In keeping with this, inhibition of this immune pathways shows protection in cellular and murine models of AD. Modulation of the microglia driven innate immune response at key signalling steps may therefore provide protection and may alter progression of disease. Therefore, antiinflammatory treatment strategies should be considered. Data on microglial activation in AD along with suggestions to modify and alter the pro- into an antiinflammatory phenotype will be reviewed and discussed.

Dr Lenore J Launer, Epidemiology to guide discovery

Using epidemiology to guide discovery: Repurposing drugs to prevent dementia - 19 June 2018

Lenore LaunerSpecial guest
Dr Lenore J. Launer
Senior Investigator, Chief, Neuroepidemiology Section
Intramural Research Program,
National Institute on Aging, NIH

Basing drug target identification on observational epidemiologic cohort studies has many unique advantages that complement other strategies for drug discovery. The case of hypertension as a risk factor for Alzheimer’s disease provides an example of using observational epidemiologic data to identify drugs that reduce AD risk. A brief overview will be given on blood pressure-brain epidemiologic and trial findings, as well as methodologic issues in studying these relationships. Preliminary data will be presented from a meta-analysis of population-based follow-up studies examining the risk for dementia-associated various anti-hypertensive medications.

Host
Dr Maksym Kopanitsa (m.kopanitsa@imperial.ac.uk)

Date and time
Tuesday 19 June 2018, 15:00 (with refreshments available from 14:30)

Venue
Praed Street seminar room, St Mary’s Faculty of Medicine Building
Directions for finding St Mary's Campus are available on the College 'Visit St Mary's' web page

Prof Seth Grant, Synaptome Mapping

Synaptome mapping: new technical approaches for unravelling the molecular architecture of synapses and the brain - 22 June 2018


Seth GrantSpecial guest
Professor Seth Grant, FRSE, FMedSci 
Centre for Clinical Brain Sciences
University of Edinburgh


Synapses are hallmarks of brain complexity – they are found in vast numbers and contain over 1,000 protein types. What is the purpose of this molecular complexity, how did it arise, and is there any logic to its organization?

We have addressed these issues using large-scale molecular approaches focused on the postsynaptic terminal of excitatory synapses. We found that postsynaptic proteins are hierarchically assembled into signalling complexes and supercomplexes, and these are distributed between synapses to generate synapse types. Whole-brain synapse maps revealed striking synaptic diversity and a “synaptome architecture” of the brain. Synaptome maps correlate with the structural and functional connectome, indicating that maps of synapse molecular diversity are features of systems-level organization.

We also analyzed the postsynaptic responses to elementary patterns of neural activity and a repertoire of innate and learned behaviours in mice with mutations in >50 postsynaptic proteins. The results of these experiments, together with the synaptome map data indicate that synapse diversity is a means of storing and recalling information in the brain. Synapse proteome complexity may generate a virtually limitless number of synapse types and synaptome maps offering immense information storage that can be accessed by patterns of activity. Autism and schizophrenia mutations disrupted the hierarchical assembly of supercomplexes and synaptome map architecture, the responses to sequences of activity and the behavioural repertoire.

Host
Dr Maksym Kopanitsa (m.kopanitsa@imperial.ac.uk)

Date and time
Friday 22 June 2018, 13:30 (with a light lunch available from 13:00)

Venue
E519, Burlington Danes Building, Hammersmith Hospital
Directions for finding Hammersmith Hospital are available on the College 'Visit Hammersmith' web page