P53-mediated heterochromatin reorganization regulates its cell fate decisions

Sathish Kumar Mungamuri; Erica Kay Benson; Shaomeng Wang; Wei Gu; Sam W. Lee; Stuart A. Aaronson

doi:10.1038/nsmb.2271

P53-mediated heterochromatin reorganization regulates its cell fate decisions

Sathish Kumar Mungamuri, Erica Kay Benson, Shaomeng Wang, Wei Gu, Sam W. Lee, Stuart A. Aaronson

Research output: Contribution to journal › Article › peer-review

43 Scopus citations

Abstract

p53 is a major sensor of cellular stresses, and its activation influences cell fate decisions. We identified SUV39H1, a histone code 'writer' responsible for the histone H3 Lys9 trimethylation (H3K9me3) mark for 'closed' chromatin conformation, as a target of p53 repression. SUV39H1 downregulation was mediated transcriptionally by p21 and post-translationally by MDM2. The H3K9me3 repression mark was found to be associated with promoters of representative p53 target genes and was decreased upon p53 activation. Overexpression of SUV39H1 maintained higher levels of the H3K9me3 mark on these promoters and was associated with decreased p53 promoter occupancy and decreased transcriptional induction in response to p53. Conversely, SUV39H1 pre-silencing decreased H3K9me3 levels on these promoters and enhanced the p53 apoptotic response. These findings uncover a new layer of p53-mediated chromatin regulation through modulation of histone methylation at p53 target promoters.

Original language	English
Pages (from-to)	478-484
Number of pages	7
Journal	Nature Structural and Molecular Biology
Volume	19
Issue number	5
DOIs	https://doi.org/10.1038/nsmb.2271
State	Published - May 2012

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title = "P53-mediated heterochromatin reorganization regulates its cell fate decisions",

abstract = "p53 is a major sensor of cellular stresses, and its activation influences cell fate decisions. We identified SUV39H1, a histone code 'writer' responsible for the histone H3 Lys9 trimethylation (H3K9me3) mark for 'closed' chromatin conformation, as a target of p53 repression. SUV39H1 downregulation was mediated transcriptionally by p21 and post-translationally by MDM2. The H3K9me3 repression mark was found to be associated with promoters of representative p53 target genes and was decreased upon p53 activation. Overexpression of SUV39H1 maintained higher levels of the H3K9me3 mark on these promoters and was associated with decreased p53 promoter occupancy and decreased transcriptional induction in response to p53. Conversely, SUV39H1 pre-silencing decreased H3K9me3 levels on these promoters and enhanced the p53 apoptotic response. These findings uncover a new layer of p53-mediated chromatin regulation through modulation of histone methylation at p53 target promoters.",

author = "Mungamuri, {Sathish Kumar} and Benson, {Erica Kay} and Shaomeng Wang and Wei Gu and Lee, {Sam W.} and Aaronson, {Stuart A.}",

note = "Funding Information: The authors would like to thank E. Bernstein and her lab members as well as C. Munoz-Fontela, M. Kracikova and W. Murk for helpful discussions. The project was supported by grant P01CA080058 from the National Cancer Institute (to S.A.A. and S.W.L.). The content of this paper is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the US National Institutes of Health.",

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AU - Lee, Sam W.

AU - Aaronson, Stuart A.

N1 - Funding Information: The authors would like to thank E. Bernstein and her lab members as well as C. Munoz-Fontela, M. Kracikova and W. Murk for helpful discussions. The project was supported by grant P01CA080058 from the National Cancer Institute (to S.A.A. and S.W.L.). The content of this paper is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the US National Institutes of Health.

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AB - p53 is a major sensor of cellular stresses, and its activation influences cell fate decisions. We identified SUV39H1, a histone code 'writer' responsible for the histone H3 Lys9 trimethylation (H3K9me3) mark for 'closed' chromatin conformation, as a target of p53 repression. SUV39H1 downregulation was mediated transcriptionally by p21 and post-translationally by MDM2. The H3K9me3 repression mark was found to be associated with promoters of representative p53 target genes and was decreased upon p53 activation. Overexpression of SUV39H1 maintained higher levels of the H3K9me3 mark on these promoters and was associated with decreased p53 promoter occupancy and decreased transcriptional induction in response to p53. Conversely, SUV39H1 pre-silencing decreased H3K9me3 levels on these promoters and enhanced the p53 apoptotic response. These findings uncover a new layer of p53-mediated chromatin regulation through modulation of histone methylation at p53 target promoters.

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P53-mediated heterochromatin reorganization regulates its cell fate decisions

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