University of Southern Denmark
A fine balance epigenetic control of cellular quiescence by the tumor suppressor PRDM2/RIZ at a bivalent domain in the cyclin a gene Cheedipudi, Sirisha; Puri, Deepika; Saleh, Amena; Gala, Hardik P; Rumman, Mohammed; Pillai, Malini S; Sreenivas, Prethish; Arora, Reety; Sellathurai, Jeeva; Schrøder, Henrik Daa; Mishra, Rakesh K; Dhawan, Jyotsna
Published in: Nucleic Acids Research
DOI: 10.1093/nar/gkv567
Publication date: 2015
Document version: Final published version
Document license: CC BY-NC
Citation for pulished version (APA): Cheedipudi, S., Puri, D., Saleh, A., Gala, H. P., Rumman, M., Pillai, M. S., Sreenivas, P., Arora, R., Sellathurai, J., Schrøder, H. D., Mishra, R. K., & Dhawan, J. (2015). A fine balance: epigenetic control of cellular quiescence by the tumor suppressor PRDM2/RIZ at a bivalent domain in the cyclin a gene. Nucleic Acids Research, 43(13), 6236-6256. https://doi.org/10.1093/nar/gkv567
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Download date: 05. Oct. 2021 6236–6256 Nucleic Acids Research, 2015, Vol. 43, No. 13 Published online 3 June 2015 doi: 10.1093/nar/gkv567 A fine balance: epigenetic control of cellular quiescence by the tumor suppressor PRDM2/RIZ at a bivalent domain in the cyclin a gene Sirisha Cheedipudi1,2,4,†, Deepika Puri1,5,†, Amena Saleh1,6, Hardik P. Gala1,2, Mohammed Rumman1,6, Malini S. Pillai1, Prethish Sreenivas1,2, Reety Arora1, Jeeva Sellathurai3, Henrik Daa Schrøder3, Rakesh K. Mishra2 and Jyotsna Dhawan1,2,*
1Institute for Stem Cell Biology and Regenerative Medicine, National Center for Biological Sciences, GKVK Post, Bellary Road, Bangalore 560065, India, 2Council of Scientific and Industrial Research-Centre for Cellular and Molecular Biology, Hyderabad 500 007, India, 3Institute of Clinical Research, SDU Muscle Research Cluster (SMRC), University of Southern Denmark, Odense 5000 C, Denmark, 4Max Planck Institute for Heart and Lung Research, Bad Nauheim 61231, Germany, 5Max Planck Institute of Immunobiology and Epigenetics, Freiburg D-79108, Germany and 6Manipal University, Manipal 576104 India
Received October 25, 2014; Revised April 23, 2015; Accepted May 19, 2015
ABSTRACT preserves key functions of the quiescent state, with implications for stem cell self-renewal. Adult stem cell quiescence is critical to ensure re- generation while minimizing tumorigenesis. Epige- netic regulation contributes to cell cycle control and INTRODUCTION differentiation, but few regulators of the chromatin Epigenetic regulatory mechanisms play a crucial role in cell state in quiescent cells are known. Here we report fate decisions, whereby global and local controls are im- that the tumor suppressor PRDM2/RIZ, an H3K9 posed on chromatin and result in distinct transcriptional methyltransferase, is enriched in quiescent muscle programs. The epi-genome of pluripotent embryonic stem stem cells in vivo and controls reversible quiescence cells (ESC) is highly permissive, accommodating both self- in cultured myoblasts. We find that PRDM2 asso- renewal and broad differentiation potential. During devel- opment, chromatin configuration becomes progressively re- ciates with >4400 promoters in G0 myoblasts, 55% of which are also marked with H3K9me2 and enriched strictive as cells commit and differentiate into specific lin- eages. Regulation at the level of chromatin is emerging as a for myogenic, cell cycle and developmental regula- primary determinant in the establishment and maintenance tors. Knockdown of PRDM2 alters histone methyla- of heritable gene expression patterns (1–4). tion at key promoters such as Myogenin and Cy- The global chromatin landscape is controlled by a hier- clinA2 (CCNA2), and subverts the quiescence pro- archy of mechanisms, of which regulation at the level of gram via global de-repression of myogenesis, and the basic unit, the nucleosome, is best understood. Inter- hyper-repression of the cell cycle. Further, PRDM2 actions of the core nucleosomal histones (H2A, H2B, H3 acts upstream of the repressive PRC2 complex in and H4) leave their N terminal tails accessible to a range G0. We identify a novel G0-specific bivalent chro- of post-translational modifications that are deposited, read matin domain in the CCNA2 locus. PRDM2 pro- or erased by a wide variety of chromatin modifying en- tein interacts with the PRC2 protein EZH2 and reg- zymes, altering the packaging of DNA. Dynamic changes ulates its association with the bivalent domain in in histone modifications can therefore also alter DNA- transcription factor interactions, and may either accom- the CCNA2 gene. Our results suggest that induc- pany or precede transcriptional activation or repression. tion of PRDM2 in G0 ensures that two antagonis- Thus, the ‘histone code’ embodies gene regulatory infor- tic programs––myogenesis and the cell cycle––while mation that is embedded in complex cell type- and cell stalled, are poised for reactivation. Together, these state-specific combinations of histone modifications (5). results indicate that epigenetic regulation by PRDM2 Typically, in addition to the requisite RNA polymerase II (pol II) binding, transcription activation correlates with tri-
*To whom correspondence should be addressed. Tel: +91-80-23666016; Fax: +91-80-2363-6662; Email: [email protected] †These authors contributed equally to the paper as first authors.