A fine balance

epigenetic control of cellular quiescence by the tumor suppressor PRDM2/RIZ at a bivalent domain in the cyclin a gene

Sirisha Cheedipudi, Deepika Puri, Amena Saleh, Hardik P Gala, Mohammed Rumman, Malini S Pillai, Prethish Sreenivas, Reety Arora, Jeeva Sellathurai, Henrik Daa Schrøder, Rakesh K Mishra, Jyotsna Dhawan

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Resumé

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.

OriginalsprogEngelsk
TidsskriftNucleic Acids Research
Vol/bind43
Udgave nummer13
Sider (fra-til)6236-6256
ISSN0305-1048
DOI
StatusUdgivet - 27. jul. 2015

Fingeraftryk

Cyclins
Epigenomics
Cell Cycle
Muscle Development
Myogenin
Neoplasms
Cell Cycle Checkpoints
Histones
Cell Differentiation
Proteins

Citer dette

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. / A fine balance : epigenetic control of cellular quiescence by the tumor suppressor PRDM2/RIZ at a bivalent domain in the cyclin a gene. I: Nucleic Acids Research. 2015 ; Bind 43, Nr. 13. s. 6236-6256.
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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.",
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author = "Sirisha Cheedipudi and Deepika Puri and Amena Saleh and Gala, {Hardik P} and Mohammed Rumman and Pillai, {Malini S} and Prethish Sreenivas and Reety Arora and Jeeva Sellathurai and Schr{\o}der, {Henrik Daa} and Mishra, {Rakesh K} and Jyotsna Dhawan",
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Cheedipudi, S, Puri, D, Saleh, A, Gala, HP, Rumman, M, Pillai, MS, Sreenivas, P, Arora, R, Sellathurai, J, Schrøder, HD, Mishra, RK & 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, bind 43, nr. 13, s. 6236-6256. https://doi.org/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. / 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.

I: Nucleic Acids Research, Bind 43, Nr. 13, 27.07.2015, s. 6236-6256.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - A fine balance

T2 - epigenetic control of cellular quiescence by the tumor suppressor PRDM2/RIZ at a bivalent domain in the cyclin a gene

AU - Cheedipudi, Sirisha

AU - Puri, Deepika

AU - Saleh, Amena

AU - Gala, Hardik P

AU - Rumman, Mohammed

AU - Pillai, Malini S

AU - Sreenivas, Prethish

AU - Arora, Reety

AU - Sellathurai, Jeeva

AU - Schrøder, Henrik Daa

AU - Mishra, Rakesh K

AU - Dhawan, Jyotsna

N1 - © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

PY - 2015/7/27

Y1 - 2015/7/27

N2 - 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.

AB - 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.

KW - Adolescent

KW - Adult

KW - Animals

KW - Cell Cycle Checkpoints

KW - Cell Differentiation

KW - Cells, Cultured

KW - Cyclin A2

KW - DNA-Binding Proteins

KW - Female

KW - G0 Phase

KW - Gene Silencing

KW - Histone-Lysine N-Methyltransferase

KW - Humans

KW - Introns

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Myoblasts, Skeletal

KW - Nuclear Proteins

KW - Polycomb Repressive Complex 2

KW - Promoter Regions, Genetic

KW - Response Elements

KW - Stem Cells

KW - Transcription Factors

KW - Tumor Suppressor Proteins

KW - Young Adult

U2 - 10.1093/nar/gkv567

DO - 10.1093/nar/gkv567

M3 - Journal article

VL - 43

SP - 6236

EP - 6256

JO - Nucleic Acids Research

JF - Nucleic Acids Research

SN - 0305-1048

IS - 13

ER -