Life Sciences Research for Lifelong Health

Mikhail Spivakov

As of July 2018, Mikhail has taken a position at the Medical Research Council's London Institute of Medical Sciences (MRC LIMS). Visit his page there for full details of his current research.

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

Disease-relevant transcriptional signatures identified in individual smooth muscle cells from healthy mouse vessels.
Dobnikar L, Taylor AL, Chappell J, Oldach P, Harman JL, Oerton E, Dzierzak E, Bennett MR, Spivakov M, Jørgensen HF

Vascular smooth muscle cells (VSMCs) show pronounced heterogeneity across and within vascular beds, with direct implications for their function in injury response and atherosclerosis. Here we combine single-cell transcriptomics with lineage tracing to examine VSMC heterogeneity in healthy mouse vessels. The transcriptional profiles of single VSMCs consistently reflect their region-specific developmental history and show heterogeneous expression of vascular disease-associated genes involved in inflammation, adhesion and migration. We detect a rare population of VSMC-lineage cells that express the multipotent progenitor marker Sca1, progressively downregulate contractile VSMC genes and upregulate genes associated with VSMC response to inflammation and growth factors. We find that Sca1 upregulation is a hallmark of VSMCs undergoing phenotypic switching in vitro and in vivo, and reveal an equivalent population of Sca1-positive VSMC-lineage cells in atherosclerotic plaques. Together, our analyses identify disease-relevant transcriptional signatures in VSMC-lineage cells in healthy blood vessels, with implications for disease susceptibility, diagnosis and prevention.

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Nature communications, 9, 2041-1723, 4567, 2018

PMID: 30385745

Genome organization and chromatin analysis identify transcriptional downregulation of insulin-like growth factor signaling as a hallmark of aging in developing B cells.
Koohy H, Bolland DJ, Matheson LS, Schoenfelder S, Stellato C, Dimond A, Várnai C, Chovanec P, Chessa T, Denizot J, Manzano Garcia R, Wingett SW, Freire-Pritchett P, Nagano T, Hawkins P, Stephens L, Elderkin S, Spivakov M, Fraser P, Corcoran AE, Varga-Weisz PD

Aging is characterized by loss of function of the adaptive immune system, but the underlying causes are poorly understood. To assess the molecular effects of aging on B cell development, we profiled gene expression and chromatin features genome-wide, including histone modifications and chromosome conformation, in bone marrow pro-B and pre-B cells from young and aged mice.

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Genome biology, 19, 1474-760X, 126, 2018

PMID: 30180872

Promoter interactome of human embryonic stem cell-derived cardiomyocytes connects GWAS regions to cardiac gene networks.
Choy MK, Javierre BM, Williams SG, Bar.oss SL, Liu Y, Wingett SW, Akbarov A, Wallace C, Freire-Pritchett P, Rugg-Gunn PJ, Spivakov M, Fraser P, Keavney BD

Long-range chromosomal interactions bring distal regulatory elements and promoters together to regulate gene expression in biological processes. By performing promoter capture Hi-C (PCHi-C) on human embryonic stem cell-derived cardiomyocytes (hESC-CMs), we show that such promoter interactions are a key mechanism by which enhancers contact their target genes after hESC-CM differentiation from hESCs. We also show that the promoter interactome of hESC-CMs is associated with expression quantitative trait loci (eQTLs) in cardiac left ventricular tissue; captures the dynamic process of genome reorganisation after hESC-CM differentiation; overlaps genome-wide association study (GWAS) regions associated with heart rate; and identifies new candidate genes in such regions. These findings indicate that regulatory elements in hESC-CMs identified by our approach control gene expression involved in ventricular conduction and rhythm of the heart. The study of promoter interactions in other hESC-derived cell types may be of utility in functional investigation of GWAS-associated regions.

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Nature communications, 9, 2041-1723, 2526, 2018

PMID: 29955040

Group Members

Latest Publications

Lineage-specific dynamic and pre-established enhancer-promoter contacts cooperate in terminal differentiation.

Rubin AJ, Barajas BC, Furlan-Magaril M

Nature genetics
1546-1718: (2017)

PMID: 28805829

Platelet function is modified by common sequence variation in megakaryocyte super enhancers.

Petersen R, Lambourne JJ, Javierre BM

Nature communications
8 2041-1723:16058 (2017)

PMID: 28703137

Dynamic Rewiring of Promoter-Anchored Chromatin Loops during Adipocyte Differentiation.

Siersbæk R, Madsen JGS, Javierre BM

Molecular cell
66 1097-4164:420-435.e5 (2017)

PMID: 28475875

Global reorganisation of cis-regulatory units upon lineage commitment of human embryonic stem cells.

Freire-Pritchett P, Schoenfelder S, Várnai C

eLife
6 2050-084X: (2017)

PMID: 28332981

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