title: The logic of transcriptional regulator recruitment architecture atcis-regulatory modules controlling liver functions.
abstract: Control of gene transcription relies on concomitant regulation by multiple transcriptional regulators (TRs). However, how recruitment of a myriad of TRs is orchestrated atcis-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 wheretrans-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.
authors.affiliation: Université Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Dubois-Chevalier
authors.affiliation: Université Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Dubois
authors.affiliation: Université Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Dehondt
authors.affiliation: The Princess Margaret Cancer Centre, University Health Network, Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Parisa
authors.initials: P
authors.lastname: Mazrooei
authors.affiliation: Université Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Mazuy
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, United Kingdom.
authors.forename: Aurélien A
authors.initials: AA
authors.lastname: Sérandour
authors.affiliation: Université Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Gheeraert
authors.affiliation: Université Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France.
authors.forename: Penderia
authors.initials: P
authors.lastname: Guillaume
authors.affiliation: Université Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Baugé
authors.affiliation: Université Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Derudas
authors.affiliation: Université Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Hennuyer
authors.affiliation: Université Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France.
authors.forename: Réjane
authors.initials: R
authors.lastname: Paumelle
authors.affiliation: Université Lille, MODAL Team, Inria Lille-Nord Europe, 59650 Villeneuve-d'Ascq, France.
authors.forename: Guillemette
authors.initials: G
authors.lastname: Marot
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, United Kingdom.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Carroll
authors.affiliation: The Princess Margaret Cancer Centre, University Health Network, Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Lupien
authors.affiliation: Université Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France.
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
authors.affiliation: Université Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Lefebvre
authors.affiliation: Université Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Eeckhoute
mesh_terms: D000465:Algorithms; D000818:Animals; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D016678:Genome; D023281:Genomics / Q000379:methods; D008099:Liver / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D047493:PPAR alpha / Q000172:deficiency / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency / Q000235:genetics; D050436:Regulatory Elements, Transcriptional; D014158:Transcription, Genetic; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D047493:PPAR alpha; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated