The logic of transcriptional regulator recruitment architecture at cis -regulatory modules controlling liver functions

Julie Dubois 1, 2 Vanessa Dubois 1, 2 Hélène Dehondt 1, 2 Parisa Mazrooei 3 Claire Mazuy 1, 2 Aurélien A. Sérandour 4 Céline Gheeraert 1, 2 Penderia Guillaume 1 Eric Baugé 1, 2 Bruno Derudas 1, 2 Nathalie Hennuyer 1, 2 Réjane Paumelle 1, 2 Guillemette Marot 5 Jason S. Carroll 4 Mathieu Lupien 3 Bart Staels 1, 2 Philippe Lefebvre 1, 2 Jerome Eeckhoute 1, 2
5 MODAL - MOdel for Data Analysis and Learning
LPP - Laboratoire Paul Painlevé - UMR 8524, Université de Lille, Sciences et Technologies, Inria Lille - Nord Europe, CERIM - Santé publique : épidémiologie et qualité des soins-EA 2694, Polytech Lille - École polytechnique universitaire de Lille
Abstract : Control of gene transcription relies on concomitant regulation by multiple transcriptional regulators (TRs). However, how recruitment of a myriad of TRs is orchestrated at cis-regulatory modules (CRMs) to account for coregulation of specific biological pathways is only partially understood. Here, we have used mouse liver CRMs involved in regulatory activities of the hepatic TR, NR1H4 (FXR; farnesoid X receptor), as our model system to tackle this question. Using integrative cistromic, epigenomic, transcriptomic, and interactomic analyses, we reveal a logical organization where trans-regulatory modules (TRMs), which consist of subsets of preferentially and coordinately corecruited TRs, assemble into hierarchical combinations at hepatic CRMs. Different combinations of TRMs add to a core TRM, broadly found across the whole landscape of CRMs, to discriminate promoters from enhancers. These combinations also specify distinct sets of CRM differentially organized along the genome and involved in regulation of either housekeeping/cellular maintenance genes or liver-specific functions. In addition to these TRMs which we define as obligatory, we show that facultative TRMs, such as one comprising core circadian TRs, are further recruited to selective subsets of CRMs to modulate their activities. TRMs transcend TR classification into ubiquitous versus liver-identity factors, as well as TR grouping into functional families. Hence, hierarchical superimpositions of obligatory and facultative TRMs bring about independent transcriptional regulatory inputs defining different sets of CRMs with logical connection to regulation of specific gene sets and biological pathways. Altogether, our study reveals novel principles of concerted transcriptional regulation by multiple TRs at CRMs.
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Submitted on : Friday, November 24, 2017 - 3:56:25 PM
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Julie Dubois, Vanessa Dubois, Hélène Dehondt, Parisa Mazrooei, Claire Mazuy, et al.. The logic of transcriptional regulator recruitment architecture at cis -regulatory modules controlling liver functions. Genome Research, Cold Spring Harbor Laboratory Press, 2017, 27 (6), pp.985 - 996. ⟨10.1101/gr.217075.116⟩. ⟨hal-01647846⟩



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