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

Abstract

Control of gene transcription relies on concomitant regulation by multiple transcriptional regulators (TR). However, how recruitment of a myriad of TR is orchestrated at cis-regulatory modules (CRM) to account for co-regulation of specific biological pathways is only partially understood. Here, we have used mouse liver CRM 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 (TRM), which consist of subsets of preferentially and co-ordinately co-recruited TR, assemble into hierarchical combinations at hepatic CRM. Different combinations of TRM add to a core TRM, broadly found across the whole landscape of CRM, 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 TRM which we define as obligatory, we show that facultative TRM, such as one comprising core circadian TR, are further recruited to selective subsets of CRM to modulate their activities. TRM transcend TR classification into ubiquitous versus liver-identity factors, as well as TR grouping into functional families. Hence, hierarchical superimpositions of obligatory and facultative TRM bring about independent transcriptional regulatory inputs defining different sets of CRM with logical connection to regulation of specific gene sets and biological pathways. Altogether, our study reveals novel principles of concerted transcriptional regulation by multiple TR at CRM.