title: The chromatin Remodeler CHD8 is required for activation of progesterone receptor-dependent enhancers.
abstract: While the importance of gene enhancers in transcriptional regulation is well established, the mechanisms and the protein factors that determine enhancers activity have only recently begun to be unravelled. Recent studies have shown that progesterone receptor (PR) binds regions that display typical features of gene enhancers. Here, we show by ChIP-seq experiments that the chromatin remodeler CHD8 mostly binds promoters under proliferation conditions. However, upon progestin stimulation, CHD8 re-localizes to PR enhancers also enriched in p300 and H3K4me1. Consistently, CHD8 depletion severely impairs progestin-dependent gene regulation. CHD8 binding is PR-dependent but independent of the pioneering factor FOXA1. The SWI/SNF chromatin-remodelling complex is required for PR-dependent gene activation. Interestingly, we show that CHD8 interacts with the SWI/SNF complex and that depletion of BRG1 and BRM, the ATPases of SWI/SNF complex, impairs CHD8 recruitment. We also show that CHD8 is not required for H3K27 acetylation, but contributes to increase accessibility of the enhancer to DNaseI. Furthermore, CHD8 was required for RNAPII recruiting to the enhancers and for transcription of enhancer-derived RNAs (eRNAs). Taken together our data demonstrate that CHD8 is involved in late stages of PR enhancers activation.
authors.affiliation: Molecular Biology Department, Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Consejo Superior de Investigaciones Científicas (CSIC), Seville, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Ceballos-Chávez
authors.affiliation: Molecular Biology Department, Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Consejo Superior de Investigaciones Científicas (CSIC), Seville, Spain.
authors.forename: Alicia
authors.initials: A
authors.lastname: Subtil-Rodríguez
authors.affiliation: Biological Sciences Department, New York City College of Technology, City University of New York, Brooklyn, New York, New York, United States of America; Arthritis and Tissue Degeneration Program and the David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, New York, United States of America.
authors.forename: Eugenia G
authors.initials: EG
authors.lastname: Giannopoulou
authors.affiliation: Centre for Genomic Regulation (CRG), Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Soronellas
authors.affiliation: Molecular Biology Department, Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Consejo Superior de Investigaciones Científicas (CSIC), Seville, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Vázquez-Chávez
authors.affiliation: Centre for Genomic Regulation (CRG), Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain.
authors.forename: Guillermo P
authors.initials: GP
authors.lastname: Vicent
authors.affiliation: HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medical College, Cornell University, New York, New York, United States of America.
authors.forename: Olivier
authors.initials: O
authors.lastname: Elemento
authors.affiliation: Centre for Genomic Regulation (CRG), Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Beato
authors.affiliation: Molecular Biology Department, Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Consejo Superior de Investigaciones Científicas (CSIC), Seville, Spain.
authors.forename: José C
authors.initials: JC
authors.lastname: Reyes
mesh_terms: D000107:Acetylation; D002843:Chromatin / Q000235:genetics; D042002:Chromatin Assembly and Disassembly / Q000235:genetics; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism; D004265:DNA Helicases / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics / Q000378:metabolism; D006801:Humans; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012319:RNA Polymerase II / Q000235:genetics; D011980:Receptors, Progesterone / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: C523331:CHD8 protein, human; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D011980:Receptors, Progesterone; D014157:Transcription Factors; D012319:RNA Polymerase II; D004265:DNA Helicases