2020-21 Seminars

23rd February: Dr Hyejung Won

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.

9th February: Dr Song Chen

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  

 

4th February: Professor Selina Wray

UK DRI Virtual Brain Meeting

Thursday 4th February 4-5pm

Professor Selina Wray

University College London

"Human stem cell models of Alzheimer's Disease"

27th January: Dr Mahmoudreza Rafiee

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 proteins in 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. 

20th January: Professor Steven Brown

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. 

15th December: Brian Schilder

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).

9th December: Dr Sam Cooke

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.

25th November: Dr Alexi Nott

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.

24th November: Dr Emmanuelle Viré

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.