“Our group aims to understand how DNA regulatory elements such as gene enhancers regulate cellular transcriptional programmes, and how their function is modified by natural genetic variation. This is important because genetic variation at enhancers is known to underlie both rare and common diseases”.
We aim to decipher the ground rules of gene control and establish their functional interplay in biological phenomena involving global changes in phenotype, such as in cell differentiation and activation. Our particular interest is in human primary cells as models, and we use genetic variation at enhancers as both experimental tools (“natural perturbations”) and objects of study in these systems.
Our analyses span multiple scales, from pairwise enhancer-promoter interactions to cis-regulatory networks, from single cells to cell populations, and from single individuals to population cohorts. We combine experimental and computational approaches in our work, capitalising on our previous studies of promoter-enhancer relationships, organisation of DNA regulatory elements and population genomics.
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.
Thiecke MJ, Wutz G, Muhar M, Tang W, Bevan S, Malysheva V, Stocsits R, Neumann T, Zuber J, Fraser P, Schoenfelder S, Peters J-M, Spivakov M. (2020). Cohesin-Dependent and -Independent Mechanisms Mediate Chromosomal Contacts between Promoters and Enhancers. Cell Reports, https://doi.org/10.1016/j.celrep.2020.107929
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.
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 data. Genome 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 history. Cell 148(3):473-86. PMID: 22304916. * joint first authors.