TY  - JOUR
A1  - Dubois-Chevalier, Julie
A1  - Dubois, Vanessa
A1  - Dehondt, Hélène
A1  - Mazrooei, Parisa
A1  - Mazuy, Claire
A1  - Sérandour, Aurélien A.
A1  - Gheeraert, Céline
A1  - Guillaume, Penderia
A1  - Baugé, Eric
A1  - Derudas, Bruno
A1  - Hennuyer, Nathalie
A1  - Paumelle, Réjane
A1  - Marot, Guillemette
A1  - Carroll, Jason S.
A1  - Lupien, Mathieu
A1  - Staels, Bart
A1  - Lefebvre, Philippe
A1  - Eeckhoute, Jérôme
T1  - The logic of transcriptional regulator recruitment architecture at cis-regulatory modules controlling liver functions
Y1  - 2017/06/01 
JF  - Genome Research 
JO  - Genome Research 
SP  - 985 
EP  - 996 
DO  - 10.1101/gr.217075.116 
VL  - 27 
IS  - 6 
UR  - http://genome.cshlp.org/content/27/6/985.abstract 
N2  - 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. 
ER  -