Dr Topher Hübel, Genetics of eating disorders
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
29 June, 15:00-16:00
Dr Marek Bartosovic
"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
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
1 June, 15:00-16:00
Dr William Lai
"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
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
"The architecture of human brain networks"
Dr Stefan Schoenfelder, Long-range enhancer-promoter
20 April 15:30-16:30
Dr Stefan Schoenfelder
"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
"Closing loops with digital health systems"
Dr Jeremy Schwartzentruber, Alzheimer’s disease risk genes
23 March 4pm-5pm
Dr Jeremy Schwartzentruber
"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 CCDC6, TSPAN14, NCK2 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 BIN1, APH1B, PTK2B, PILRA 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
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
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
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
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
15th December 4-5pm
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
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.