title: A fine balance: epigenetic control of cellular quiescence by the tumor suppressor PRDM2/RIZ at a bivalent domain in the cyclin a gene.
abstract: Adult stem cell quiescence is critical to ensure regeneration while minimizing tumorigenesis. Epigenetic regulation contributes to cell cycle control and differentiation, but few regulators of the chromatin state in quiescent cells are known. Here we report that the tumor suppressor PRDM2/RIZ, an H3K9 methyltransferase, is enriched in quiescent muscle stem cells in vivo and controls reversible quiescence in cultured myoblasts. We find that PRDM2 associates with >4400 promoters in G0 myoblasts, 55% of which are also marked with H3K9me2 and enriched for myogenic, cell cycle and developmental regulators. Knockdown of PRDM2 alters histone methylation at key promoters such as Myogenin and CyclinA2 (CCNA2), and subverts the quiescence program via global de-repression of myogenesis, and hyper-repression of the cell cycle. Further, PRDM2 acts upstream of the repressive PRC2 complex in G0. We identify a novel G0-specific bivalent chromatin domain in the CCNA2 locus. PRDM2 protein interacts with the PRC2 protein EZH2 and regulates its association with the bivalent domain in the CCNA2 gene. Our results suggest that induction of PRDM2 in G0 ensures that two antagonistic programs-myogenesis and the cell cycle-while stalled, are poised for reactivation. Together, these results indicate that epigenetic regulation by PRDM2 preserves key functions of the quiescent state, with implications for stem cell self-renewal.
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, National Center for Biological Sciences, GKVK Post, Bellary Road, Bangalore 560065, India Council of Scientific and Industrial Research-Centre for Cellular and Molecular Biology, Hyderabad 500 007, India Max Planck Institute for Heart and Lung Research, Bad Nauheim 61231, Germany.
authors.forename: Sirisha
authors.initials: S
authors.lastname: Cheedipudi
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, National Center for Biological Sciences, GKVK Post, Bellary Road, Bangalore 560065, India Max Planck Institute of Immunobiology and Epigenetics, Freiburg D-79108, Germany.
authors.forename: Deepika
authors.initials: D
authors.lastname: Puri
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, National Center for Biological Sciences, GKVK Post, Bellary Road, Bangalore 560065, India Manipal University, Manipal 576104 India.
authors.forename: Amena
authors.initials: A
authors.lastname: Saleh
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, National Center for Biological Sciences, GKVK Post, Bellary Road, Bangalore 560065, India Council of Scientific and Industrial Research-Centre for Cellular and Molecular Biology, Hyderabad 500 007, India.
authors.forename: Hardik P
authors.initials: HP
authors.lastname: Gala
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, National Center for Biological Sciences, GKVK Post, Bellary Road, Bangalore 560065, India Manipal University, Manipal 576104 India.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Rumman
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, National Center for Biological Sciences, GKVK Post, Bellary Road, Bangalore 560065, India.
authors.forename: Malini S
authors.initials: MS
authors.lastname: Pillai
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, National Center for Biological Sciences, GKVK Post, Bellary Road, Bangalore 560065, India Council of Scientific and Industrial Research-Centre for Cellular and Molecular Biology, Hyderabad 500 007, India.
authors.forename: Prethish
authors.initials: P
authors.lastname: Sreenivas
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, National Center for Biological Sciences, GKVK Post, Bellary Road, Bangalore 560065, India.
authors.forename: Reety
authors.initials: R
authors.lastname: Arora
authors.affiliation: Institute of Clinical Research, SDU Muscle Research Cluster (SMRC), University of Southern Denmark, Odense 5000 C, Denmark.
authors.forename: Jeeva
authors.initials: J
authors.lastname: Sellathurai
authors.affiliation: Institute of Clinical Research, SDU Muscle Research Cluster (SMRC), University of Southern Denmark, Odense 5000 C, Denmark.
authors.forename: Henrik Daa
authors.initials: HD
authors.lastname: Schrøder
authors.affiliation: Council of Scientific and Industrial Research-Centre for Cellular and Molecular Biology, Hyderabad 500 007, India.
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Mishra
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, National Center for Biological Sciences, GKVK Post, Bellary Road, Bangalore 560065, India Council of Scientific and Industrial Research-Centre for Cellular and Molecular Biology, Hyderabad 500 007, India jdhawan@ncbs.res.in.
authors.forename: Jyotsna
authors.initials: J
authors.lastname: Dhawan
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D059447:Cell Cycle Checkpoints; D002454:Cell Differentiation; D002478:Cells, Cultured; D056751:Cyclin A2 / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D020868:Gene Silencing; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006801:Humans; D007438:Introns; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032448:Myoblasts, Skeletal / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism; D011401:Promoter Regions, Genetic; D020218:Response Elements; D016192:Resting Phase, Cell Cycle / Q000235:genetics*; D013234:Stem Cells / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D055815:Young Adult
chemical_list: C508184:CCNA2 protein, mouse; D056751:Cyclin A2; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000071221:Enhancer of Zeste Homolog 2 Protein; C498408:Ezh1 protein, mouse; C498410:Ezh2 protein, mouse; D011495:Histone-Lysine N-Methyltransferase; C093563:PRDM2 protein, human; D063151:Polycomb Repressive Complex 2; C489242:Prdm2 protein, mouse