title: RBFox2 Binds Nascent RNA to Globally Regulate Polycomb Complex 2 Targeting in Mammalian Genomes.
abstract: Increasing evidence suggests that diverse RNA binding proteins (RBPs) interact with regulatory RNAs to regulate transcription. RBFox2 is a well-characterized pre-mRNA splicing regulator, but we now encounter an unexpected paradigm where depletion of this RBP induces widespread increase in nascent RNA production in diverse cell types. Chromatin immunoprecipitation sequencing (ChIP-seq) reveals extensive interaction of RBFox2 with chromatin in a nascent RNA-dependent manner. Bayesian network analysis connects RBFox2 to Polycomb complex 2 (PRC2) and H3K27me3, and biochemical experiments demonstrate the ability of RBFox2 to directly interact with PRC2. Strikingly, RBFox2 inactivation eradicates PRC2 targeting on the majority of bivalent gene promoters and leads to transcriptional de-repression. Together, these findings uncover a mechanism underlying the enigmatic association of PRC2 with numerous active genes, highlight the importance of gene body sequences to gauge transcriptional output, and suggest nascent RNAs as critical signals for transcriptional feedback control to maintain homeostatic gene expression in mammalian genomes.
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093-0651, USA.
authors.forename: Chaoliang
authors.initials: C
authors.lastname: Wei
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093-0651, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Xiao
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093-0651, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093-0651, USA; Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China.
authors.forename: Hanwei
authors.initials: H
authors.lastname: Cui
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093-0651, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093-0651, USA.
authors.forename: Yuanchao
authors.initials: Y
authors.lastname: Xue
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093-0651, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093-0651, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Zhou
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093-0651, USA.
authors.forename: Taiki
authors.initials: T
authors.lastname: Tsutsui
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093-0651, USA.
authors.forename: Jinsong
authors.initials: J
authors.lastname: Qiu
authors.affiliation: Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China.
authors.forename: Hairi
authors.initials: H
authors.lastname: Li
authors.affiliation: Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China.
authors.forename: Liling
authors.initials: L
authors.lastname: Tang
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093-0651, USA; Institute of Genomic Medicine, University of California, San Diego, La Jolla, CA 92093-0651, USA. Electronic address: xdfu@ucsd.edu.
authors.forename: Xiang-Dong
authors.initials: XD
authors.lastname: Fu
mesh_terms: D000818:Animals; D001499:Bayes Theorem; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D016678:Genome; D005838:Genotype; D057809:HEK293 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D018345:Mice, Knockout; D008957:Models, Genetic; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010641:Phenotype; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012313:RNA / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D000072260:RNA Splicing Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D002843:Chromatin; D006657:Histones; C454924:RBFOX2 protein, human; D000072260:RNA Splicing Factors; C558929:Rbfox2 protein, mouse; D012097:Repressor Proteins; D012313:RNA; D063151:Polycomb Repressive Complex 2