Life Sciences Research for Lifelong Health

Mikhail Spivakov

Research Summary

Cells in the body share their genetic code, but look and function differently. This is largely because many genes are only active in specific cell types and under certain environmental conditions.

Gene regulation converges at DNA regulatory modules – molecular "switches" that are encoded on the DNA alongside protein-coding genes. These modules recruit combinations of proteins and establish three-dimensional interactions required for gene activity or repression.

In contrast to the striking simplicity of the genetic code at protein-coding regions, the logic underlying the organisation of DNA regulatory modules still remains to be fully understood.

It is important to learn more about it, particularly because we now know that many healthy and pathological traits are associated with genetic variation at regulatory (rather than protein-coding) regions.

Latest Publications

Lineage-Specific Genome Architecture Links Enhancers and Non-coding Disease Variants to Target Gene Promoters.
Javierre BM, Burren OS, Wilder SP, Kreuzhuber R, Hill SM, Sewitz S, Cairns J, Wingett SW, Várnai C, Thiecke MJ, Burden F, Farrow S, Cutler AJ, Rehnström K, Downes K, Grassi L, Kostadima M, Freire-Pritchett P, Wang F, , Stunnenberg HG, Todd JA, Zerbino DR, Stegle O, Ouwehand WH, Frontini M, Wallace C, Spivakov M, Fraser P

Long-range interactions between regulatory elements and gene promoters play key roles in transcriptional regulation. The vast majority of interactions are uncharted, constituting a major missing link in understanding genome control. Here, we use promoter capture Hi-C to identify interacting regions of 31,253 promoters in 17 human primary hematopoietic cell types. We show that promoter interactions are highly cell type specific and enriched for links between active promoters and epigenetically marked enhancers. Promoter interactomes reflect lineage relationships of the hematopoietic tree, consistent with dynamic remodeling of nuclear architecture during differentiation. Interacting regions are enriched in genetic variants linked with altered expression of genes they contact, highlighting their functional role. We exploit this rich resource to connect non-coding disease variants to putative target promoters, prioritizing thousands of disease-candidate genes and implicating disease pathways. Our results demonstrate the power of primary cell promoter interactomes to reveal insights into genomic regulatory mechanisms underlying common diseases.

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Cell, 167, 1097-4172, 1369-1384.e19, 2016

PMID: 27863249

Defining cell type with chromatin profiling.
Spivakov M, Fraser P

Nature biotechnology, 34, 1546-1696, 1126-1128, 2016

PMID: 27824844

Integrating epigenomic data and 3D genomic structure with a new measure of chromatin assortativity.
Pancaldi V, Carrillo-de-Santa-Pau E, Javierre BM, Juan D, Fraser P, Spivakov M, Valencia A, Rico D

Network analysis is a powerful way of modeling chromatin interactions. Assortativity is a network property used in social sciences to identify factors affecting how people establish social ties. We propose a new approach, using chromatin assortativity, to integrate the epigenomic landscape of a specific cell type with its chromatin interaction network and thus investigate which proteins or chromatin marks mediate genomic contacts.

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Genome biology, 17, 1474-760X, 152, 0

PMID: 27391817

Group Members

Latest Publications

Lineage-Specific Genome Architecture Links Enhancers and Non-coding Disease Variants to Target Gene Promoters.

Javierre BM, Burren OS, Wilder SP

Cell
167 1097-4172:1369-1384.e19 (2016)

PMID: 27863249

Defining cell type with chromatin profiling.

Spivakov M, Fraser P

Nature biotechnology
34 1546-1696:1126-1128 (2016)

PMID: 27824844

Integrating epigenomic data and 3D genomic structure with a new measure of chromatin assortativity.

Pancaldi V, Carrillo-de-Santa-Pau E, Javierre BM

Genome biology
17 1474-760X:152 (0)

PMID: 27391817

CHiCAGO: robust detection of DNA looping interactions in Capture Hi-C data.

Cairns J, Freire-Pritchett P, Wingett SW

Genome biology
17 1474-760X:127 (2016)

PMID: 27306882

Two Mutually Exclusive Local Chromatin States Drive Efficient V(D)J Recombination.

Bolland DJ, Koohy H, Wood AL

Cell reports
15 2211-1247:2475-87 (2016)

PMID: 27264181

CHiCP: a web-based tool for the integrative and interactive visualization of promoter capture Hi-C datasets.

Schofield EC, Carver T, Achuthan P

Bioinformatics (Oxford, England)
32 1367-4811:2511-3 (2016)

PMID: 27153610

Dynamic Reorganization of Extremely Long-Range Promoter-Promoter Interactions between Two States of Pluripotency.

Joshi O, Wang SY, Kuznetsova T

Cell stem cell
17 1875-9777:748-57 (2015)

PMID: 26637943