Interplay of cis and trans mechanisms driving transcription factor binding and gene expression evolution
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Authors
Wong, Emily S
Schmitt, Bianca M
Kazachenka, Anastasiya
Thybert, David
Redmond, Aisling
Connor, Frances
Rayner, Tim F
Flicek, Paul
Publication Date
2017-10-23Journal Title
Nature Communications
ISSN
2041-1723
Publisher
Springer Nature
Volume
8
Number
1092
Language
eng
Type
Article
This Version
VoR
Metadata
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Wong, E. S., Schmitt, B. M., Kazachenka, A., Thybert, D., Redmond, A., Connor, F., Rayner, T. F., et al. (2017). Interplay of cis and trans mechanisms driving transcription factor binding and gene expression evolution. Nature Communications, 8 (1092)https://doi.org/10.1038/s41467-017-01037-x
Abstract
Noncoding regulatory variants play a central role in the genetics of human diseases and in evolution. Here we measure allele-specific transcription factor binding occupancy of three liver-specific transcription factors between crosses of two inbred mouse strains to elucidate the regulatory mechanisms underlying transcription factor binding variations in mammals. Our results highlight the pre-eminence of cis-acting variants on transcription factor occupancy divergence. Transcription factor binding differences linked to cis-acting variants generally exhibit additive inheritance, while those linked to trans-acting variants are most often dominantly inherited. Cis-acting variants lead to local coordination of transcription factor occupancies that decay with distance; distal coordination is also observed and may be modulated by long-range chromatin contacts. Our results reveal the regulatory mechanisms that interplay to drive transcription factor occupancy, chromatin state, and gene expression in complex mammalian cell states.
Sponsorship
We thank the CRUK—CI Genomics, BRU, and Bioinformatics Cores for technical assistance and the EMBL-EBI systems team for management of computational resources. This research was supported by the European Molecular Biology Laboratory (E.S.W., D.T., J.C.M., P.F.), Cancer Research UK (B.M.S., T.F.R., F.C., C.F., A.R., D.T.O.), the BOLD ITN (B.M.S.), Darwin Fellowship (A.K.), the Wellcome Trust (WT202878/B/16/Z, WT108749/Z/15/Z) (P.F.), (WT202878/A/16/Z) (D.T.O), (WT095606) (A.C.F.-S) and (WT098051) (P.F., D.T.O.), EMBO Long-term (ALTF1518-2012) and Advanced Fellowships (aALTF1672-2014) (E.S.W.), and by the European Research Council (award 615584) and EMBO Young Investigator Programme (D.T.O.).
Funder references
European Research Council (615584)
Wellcome Trust (095606/Z/11/Z)
Cancer Research UK (20412)
Wellcome Trust (202878/Z/16/Z)
Identifiers
External DOI: https://doi.org/10.1038/s41467-017-01037-x
This record's URL: https://www.repository.cam.ac.uk/handle/1810/270601
Rights
Attribution 4.0 International, Attribution 4.0 International
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