title: Mediator complex cooperatively regulates transcription of retinoic acid target genes with Polycomb Repressive Complex 2 during neuronal differentiation.
abstract: The Mediator complex (Mediator) plays key roles in transcription and functions as the nexus for integration of various transcriptional signals. Previously, we screened for Mediator cyclin-dependent kinase (CDK)-interacting factors and identified three proteins related to chromatin regulation. One of them, SUZ12 is required for both stability and activity of Polycomb Repressive Complex 2 (PRC2). PRC2 primarily suppresses gene expression through histone H3 lysine 27 trimethylation, resulting in stem cell maintenance and differentiation; perturbation of this process leads to oncogenesis. Recent work showed that Mediator contributes to the embryonic stem cell state through DNA loop formation, which is strongly associated with chromatin architecture; however, it remains unclear how Mediator regulates gene expression in cooperation with chromatin regulators (i.e. writers, readers and remodelers). We found that Mediator CDKs interact directly with the PRC2 subunit EZH2, as well as SUZ12. Known PRC2 target genes were deregulated by Mediator CDK knockdown during neuronal differentiation, and both Mediator and PRC2 complexes co-occupied the promoters of developmental genes regulated by retinoic acid. Our results provide a mechanistic link between Mediator and PRC2 during neuronal differentiation.
authors.affiliation: Laboratory of Gene Regulation, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan;
authors.forename: Rikiya
authors.initials: R
authors.lastname: Fukasawa
authors.affiliation: Laboratory of Gene Regulation, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan;
authors.forename: Satoshi
authors.initials: S
authors.lastname: Iida
authors.affiliation: Laboratory of Gene Regulation, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan; Department of Cellular and Molecular Medicine, UCSD School of Medicine, 9500 Gilman Drive, La Jolla, California 92093, USA; and.
authors.forename: Taiki
authors.initials: T
authors.lastname: Tsutsui
authors.affiliation: Laboratory of Gene Regulation, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan;
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Hirose
authors.affiliation: Laboratory of Gene Regulation, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan; Department of Biochemistry, Nagasaki University School of Medicine, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan ohkumay@pha.u-toyama.ac.jp.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Ohkuma
mesh_terms: D000818:Animals; D002460:Cell Line; D056850:Cyclin-Dependent Kinase 8 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D054278:Embryonal Carcinoma Stem Cells / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D000071221:Enhancer of Zeste Homolog 2 Protein; D017353:Gene Deletion; D006801:Humans; D051379:Mice; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D055495:Neurogenesis; D010766:Phosphorylation; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011494:Protein Kinases / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D034622:RNA Interference; D012319:RNA Polymerase II / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014157:Transcription Factors; D014158:Transcription, Genetic; D014212:Tretinoin / Q000378:metabolism*
chemical_list: D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D011993:Recombinant Fusion Proteins; C430461:SUZ12 protein, human; D014157:Transcription Factors; D014212:Tretinoin; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D011494:Protein Kinases; C060137:carboxy-terminal domain kinase; C584437:CDK19 protein, human; C095686:CDK8 protein, human; D056850:Cyclin-Dependent Kinase 8; D018844:Cyclin-Dependent Kinases; D012319:RNA Polymerase II
keywords: PRC2; chromatin regulation; mediator; neuronal differentiation; transcriptional regulation