Functional Gene Control

MikhailSpivakov

Mikhail Spivakov

Contact Details

Funding

MRC logo

“We are interested in how genomic and epigenetic information is integrated with extrinsic signals to promote concerted changes in gene expression”.

Part of the “core autoimmune disease network” of genes showing associations with different autoimmune diseases (colour-coded as shown) based on integrating GWAS data with chromosomal interactions between GWAS-detected non-coding SNPs and gene promoters in a panel of human primary blood cells. Edges between genes are drawn based on prior knowledge on their physical or functional relationships and are colour-coded accordingly. Adapted from Javierre et al., Cell 2016.

We aim to decipher the ground rules of gene regulation and establish their functional interplay in biological phenomena involving global changes in phenotype, such as in cell differentiation and activation. Our current focus is on the role of non-coding DNA elements such as enhancers in integrating and transmitting gene regulatory information.

We combine experimental and computational approaches to study these questions, capitalising on our previous work on promoter-enhancer relationships, organisation of DNA regulatory elements and population genomics. Our particular interest is in human primary cells as models, and in genetic and epigenetic variation as “natural perturbations” in the system.

Our ultimate goal is to generate comprehensive functional models of gene control “logic” underlying cellular decisions. Interrogation and validation of these models will pinpoint key individual players (regulatory elements, genes, extrinsic signals) and their regulatory relationships in these processes and shed light on how they are remodelled in disease.

Chromosomal interactions (shown as arcs) of SOX2 gene promoter in human embryonic stem cells (upper) and neural progenitor cells (lower) detected using Promoter Capture Hi-C. Also shown is information on gene expression (mRNA-seq), the patterns of histone modifications, and chromatin states defined jointly on their basis (active chromatin, green; poised chromatin, orange; Polycomb-repressed, red; intermediate, yellow; background, grey). Adapted from Freire-Pritchett et al., eLife 2017.

Selected Publications

Dobnikar L* / Taylor AL*, Chappell J, Oldach P, Harman JL, Oerton E, Dzierzak E, Bennett MR, Spivakov M^ / Jørgensen HF^. Disease-relevant transcriptional signatures identified in individual smooth muscle cells from healthy mouse vessels. Nature Communications, 2018. 9:4567.

* – joint first authors, ^ – joint corresponding authors and supervisors.

Freire-Pritchett P* / Schoenfelder S*, Várnai C, Wingett SW, Cairns J, Collier AJ, García-Vílchez R, Furlan-Magaril M, Osborne CS, Fraser P, Rugg-Gunn PJ^, Spivakov M^. (2017). Global reorganisation of cis-regulatory units upon lineage commitment of human embryonic stem cells. eLife 6. doi: 10.7554/eLife.21926.

* joint first authors, ^ joint corresponding authors.

Javierre B-M* / 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, The BLUEPRINT Consortium , Stunnenberg HG, Todd JA, Zerbino DR, Stegle O, Ouwehand WH, Frontini M^ / Wallace C^ / Spivakov M^# / Fraser P^. (2016). Lineage-specific genome architecture links enhancers and non-coding disease variants to target gene promoters Cell 167(5), 1369-1384.

* joint first authors, ^ joint corresponding authors, # lead contact.
•  Minireview presenting this paper    •  Interview on Cambridge TV

Cairns J* / Freire-Pritchett P*, Wingett SW, Várnai C, Dimond A, Plagnol V, Zerbino D, Schoenfelder S, Javierre B-M, Osborne C, Fraser P, Spivakov M. (2016). CHiCAGO: Robust Detection of DNA Looping Interactions in Capture Hi-C dataGenome Biology 17(1), 127. PMID: 27306882.

F1000 Prime recommended paper. * joint first authors.

Bolland DJ* / Koohy H*, Wood AL, Matheson LS, Krueger F, Stubbington MJT, Baizan-Edge A, Chovanec P, Stubbs BA, Tabbada K, Andrews SR, Spivakov M^, Corcoran AE^. (2016). Two Mutually Exclusive Local Chromatin States Drive Efficient V(D)J Recombination. Cell Reports 15(11), 2475–2487. PMID: 27264181.

F1000 Prime recommended paper. * joint first authors; ^ joint corresponding authors.

Spivakov M. (2014). Spurious transcription factor binding: Non-functional or genetically redundant? BioEssays 36(8), 798-806. PMID: 24888900.

Junion G* / Spivakov M*, Girardot C, Braun M, Gustafson EH, Birney E, Furlong EE. (2012). A transcription factor collective defines cardiac cell fate and reflects lineage historyCell 148(3):473-86. PMID: 22304916. * joint first authors.