The logic of transcriptional regulator recruitment architecture at cis-regulatory modules controlling liver functions
Open accessAbstract
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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Hepatic TF cistromes can be faithfully inferred from mouse liver ChIP-seq data.
“hepatic TF cistromes can be faithfully inferred from mouse liver ChIP‐seq data (Kyrmizi et al, 2006; Schmidt et al, 2010; Dubois‐Chevalier et al, 2017a; Sommars et al, 2019; Dubois et al, 2020a).”
From An extended transcription factor regulatory network controls hepatocyte identity (2023) · cites this paper as Dubois‐Chevalier et al, 2017a
The Results section on NR1H4-bound CRMs describes using mouse-liver ChIP-seq data to define the NR1H4 cistrome and compare it with 47 other transcriptional regulators. The Methods section on ChIP-seq processing describes replicate and false-positive controls. These passages support deriving hepatic regulator cistromes from mouse-liver ChIP-seq, but do not establish that the resulting cistromes can be inferred *faithfully* in general. (LLM, conf=0.81)
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Cites
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An extended transcription factor regulatory network controls hepatocyte identity
Dubois‐Chevalier, J., Gheeraert, C., Berthier, A., Boulet, C., Dubois, V., Guille, L., Fourcot, M., Marot, G., Gauthier, K., Dubuquoy, L., et al. (2023) · EMBO Reports · doi:10.15252/embr.202357020 · Cited by 6 · see citing works
“Calling of super-enhancers (SE) and target gene assignation, essentially performed as in (Loven et al , 2013; Whyte et al , 2013), was previously described (Dubois-Chevalier et al , 2020).”
Self-citation
- Authors
- Dubois-Chevalier, J., Dubois, V., Dehondt, H., Mazrooei, P., Mazuy, C., Sérandour, A. A., Gheeraert, C., Guillaume, P., Baugé, E., Derudas, B., Hennuyer, N., Paumelle, R., Marot, G., Carroll, J. S., Lupien, M., Staels, B., Lefebvre, P., & Eeckhoute, J.
- Affiliations
- Inserm (FR)
- University Health Network (CA)
- University of Cambridge (GB)
- Institut national de recherche en sciences et technologies du numérique (FR)
- ORCID
- Venue
- Genome Research
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2017-04-11
- Volume
- 27
- Issue
- 6
- Pages
- 985-996
- ISSN
- 1088-9051 (ISSN-L)
- 1549-5469
- PMC
- PMC5453331
- OpenAlex
- W2606155821
- Cited by
- 29
- References
- 8
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2023: 9 · 2022: 4 · 2020: 4 · 2019: 1 · 2018: 5 · 2017: 2
- Type
- posted content
- Language
- en
- Open access
- hybrid
- doi.org
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- other-oa
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- Genome Research (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- HAL (submittedVersion, cc-by-nc)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- LillOA (Université de Lille (University Of Lille)) (submittedVersion, cc-by-nc)
- LillOA (Université de Lille (University Of Lille)) (submittedVersion, other-oa)
- HighWire Press Open Archive (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion, cc-by-nc)
- Apollo
- Funders
- Fondation pour la Recherche Médicale (DEQ20150331724)
- European Genomic Institute for Diabetes
- Agence Nationale de la Recherche (ANR-10-LABX-46)
- European Commission
- Institut Universitaire de France
- European Research Council (694717)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
- Keywords
- transcription factors, cis-regulatory modules, farnesoid X receptor, liver gene regulation, co-regulation, enhancers, promoter, hepatic gene expression
- MeSH terms
- Receptor, Farnesoid X-Activated, Algorithms, Animals, Gene Expression Regulation, Liver, Transcription, Genetic, Genome, Receptors, Cytoplasmic and Nuclear, Mice, Knockout, Gene Expression Profiling, Genomics, PPAR alpha, Regulatory Elements, Transcriptional, Mice
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