Probing the functional effects of genetic variation at enhancers with 3D genomics
https://profiles.imperial.ac.uk/mikhail.spivakov/about
Summary
Over the last decade, our team has studied enhancer-promoter communication in multiple human systems, capitalising on high-resolution Capture Hi-C. Recently, we have developed a miniaturised version of this assay and evolved the computational tools for Capture Hi-C data analysis and integration with population genetic data. I will present our work using these technologies to (a) leverage natural genetic variation to functionally dissect the relationship between the activity and connectivity of enhancers and (b) link disease-associated variants with target genes in a rare cell type, Type 3 Innate Lymphoid Cells, leading to the identification of a surprising gene candidate for Crohn's disease.
Key publications relevant to the talk:
Ray-Jones H#, Song Z, Haglund A, Artemov P, …, Frontini M, Wallace C, Malysheva V$, Bottolo L$, Vigorito E$, Spivakov M$,#. Shared and distinct molecular effects of regulatory genetic variants provide insight into mechanisms of distal enhancer-promoter communication. bioRxiv, 2023.08.04.551251. (# Joint corresponding authors; $ Joint senior authors)
Malysheva V# / Ray-Jones H, …, Wallace C, Miraldi E, Waggoner S, Spivakov M#. High resolution promoter interaction analysis in Type 3 Innate Lymphoid Cells implicates Batten Disease gene CLN3 in Crohn’s Disease aetiology. bioRxiv, 2022.10.19.512842. (# Joint corresponding authors)
Thiecke M / Wutz G, Muhar M, …, Stocsits R, Neumann T, Zuber J, Fraser P, Schoenfelder S, Peters J-M, Spivakov M. Cohesin-dependent and independent mechanisms support chromosomal contacts between promoters and enhancers. Cell Reports, 2020. 32, 107929.
Freire-Pritchett P / Ray-Jones H, Della Rosa M, Eijsbouts C, Orchard WR, Wingett SW, Wallace C, Cairns J, Spivakov M#, Malysheva V#. Detecting chromosomal interactions in Capture Hi-C data with CHiCAGO and companion tools. Nature Protocols, 2021. 16:4144-4176. (# Joint corresponding authors).
Mitchelmore J, Grinberg N, Wallace C, Spivakov M. Functional effects of variation in transcription factor binding highlight long-range gene regulation by epromoters. Nucleic Acids Res, 2020. 48, 2866–2879.
Javierre BM / Burren O / Wilder S / Kreuzhuber R / Hill S, …, Ouwehand WH, Frontini M#, Wallace C#, Spivakov M#^, Fraser P#. Lineage-specific genome architecture links enhancers and non-coding disease variants to target gene promoters. Cell. 2016. 147: 1369–1384. (# Joint corresponding author; ^ Lead contact).