title: Dissecting the Rev-erbα Cistrome and the Mechanisms Controlling Circadian Transcription in Liver.
abstract: Circadian clocks maintain whole-body metabolic homeostasis by coordinating rhythmic gene expression in multiple tissues. Core clock regulators sustain their own oscillation and confer expression rhythmicity on clock-controlled genes (CCGs). Our unbiased examination of enhancer RNA (eRNA) transcription around the clock in mouse liver identified functional enhancers of circadian genes driven by phase-specific transcription factors (TFs). Rev-erbα emerged as a primary driver of circadian enhancers, leading to oscillating gene expression in opposite phases through direct and indirect regulation. Among Rev-erbα target genes were core clock components and metabolic CCGs. Oscillation of clock genes was enforced by direct competition between Rev-erbα and RORα for binding to cognate motifs in the genome, whereas metabolic CCGs were governed by recruitment of the NCoR/HDAC3 complex to enhancers where Rev-erbα is tethered by tissue-specific TFs. The DNA sequence-mediated competition between Rev-erbα and RORα ensures consistent clock control across all tissues. In contrast, the tethered binding mechanism is tissue-specific and thus allows Rev-erbα to dictate an epigenomic rhythm tailored to the specific need of that tissue. Therefore, discrete modes of recruitment allow Rev-erbα to link the clock to cell-specific functions, including metabolism.
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine and Department of Genetics, and The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Bin
authors.initials: B
authors.lastname: Fang
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine and Department of Genetics, and The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Mitchell A
authors.initials: MA
authors.lastname: Lazar
mesh_terms: D000818:Animals; D002940:Circadian Rhythm / Q000235:genetics*; D004742:Enhancer Elements, Genetic / Q000235:genetics; D063185:Epigenetic Repression / Q000235:genetics; D005786:Gene Expression Regulation; D006655:Histone Deacetylases / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D051379:Mice; D056971:Nuclear Receptor Co-Repressor 1 / Q000378:metabolism; D056985:Nuclear Receptor Co-Repressor 2 / Q000378:metabolism; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000235:genetics*; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic; D000099186:Histone Deacetylase 3
chemical_list: D006655:Histone Deacetylases; D056971:Nuclear Receptor Co-Repressor 1; D056985:Nuclear Receptor Co-Repressor 2; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D014157:Transcription Factors; D000099186:Histone Deacetylase 3