Reversible methylation of promoter-bound STAT3 by histone-modifying enzymes

Jinbo Yang, Jing Huang, Maupali Dasgupta, Nathan Sears, Masaru Miyagi, Benlian Wang, Mark R. Chance, Xing Chen, Yuping Du, Yuxin Wang, Lizhe An, Qin Wang, Tao Lu, Xiaodong Zhang, Zhenghe Wang, George R. Stark

Research output: Contribution to journalArticle

160 Citations (Scopus)

Abstract

Following its tyrosine phosphorylation, STAT3 is methylated on K140 by the histone methyl transferase SET9 and demethylated by LSD1 when it is bound to a subset of the promoters that it activates. Methylation of K140 is a negative regulatory event, because its blockade greatly increases the steady-state amount of activated STAT3 and the expression of many (i.e., SOCS3) but not all (i.e., CD14) STAT3 target genes. Biological relevance is shown by the observation that overexpression of SOCS3 when K140 cannot be methylated blocks the ability of cells to activate STAT3 in response to IL-6. K140 methylation does not occur with mutants of STAT3 that do not enter nuclei or bind to DNA. Following treatment with IL-6, events at the SOCS3 promoter occur in an ordered sequence, as shown by chromatin immunoprecipitations. Y705-phosphoryl- STAT3 binds first and S727 is then phosphorylated, followed by the coincident binding of SET9 and dimethylation of K140, and lastly by the binding of LSD1. We conclude that the lysine methylation of promoter-bound STAT3 leads to biologically important down-regulation of the dependent responses and that SET9, which is known to help provide an activating methylation mark to H3K4, is recruited to the newly activated SOCS3 promoter by STAT3.

Original languageEnglish (US)
Pages (from-to)21499-21504
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number50
DOIs
StatePublished - Dec 14 2010
Externally publishedYes

Fingerprint

Histones
Methylation
Enzymes
Interleukin-6
Chromatin Immunoprecipitation
Transferases
Lysine
Tyrosine
Down-Regulation
Phosphorylation
DNA
Genes

Keywords

  • Gene regulation
  • Posttranslational modifications
  • Signal transduction

ASJC Scopus subject areas

  • General

Cite this

Reversible methylation of promoter-bound STAT3 by histone-modifying enzymes. / Yang, Jinbo; Huang, Jing; Dasgupta, Maupali; Sears, Nathan; Miyagi, Masaru; Wang, Benlian; Chance, Mark R.; Chen, Xing; Du, Yuping; Wang, Yuxin; An, Lizhe; Wang, Qin; Lu, Tao; Zhang, Xiaodong; Wang, Zhenghe; Stark, George R.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 50, 14.12.2010, p. 21499-21504.

Research output: Contribution to journalArticle

Yang, J, Huang, J, Dasgupta, M, Sears, N, Miyagi, M, Wang, B, Chance, MR, Chen, X, Du, Y, Wang, Y, An, L, Wang, Q, Lu, T, Zhang, X, Wang, Z & Stark, GR 2010, 'Reversible methylation of promoter-bound STAT3 by histone-modifying enzymes', Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 50, pp. 21499-21504. https://doi.org/10.1073/pnas.1016147107
Yang, Jinbo ; Huang, Jing ; Dasgupta, Maupali ; Sears, Nathan ; Miyagi, Masaru ; Wang, Benlian ; Chance, Mark R. ; Chen, Xing ; Du, Yuping ; Wang, Yuxin ; An, Lizhe ; Wang, Qin ; Lu, Tao ; Zhang, Xiaodong ; Wang, Zhenghe ; Stark, George R. / Reversible methylation of promoter-bound STAT3 by histone-modifying enzymes. In: Proceedings of the National Academy of Sciences of the United States of America. 2010 ; Vol. 107, No. 50. pp. 21499-21504.
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AU - Yang, Jinbo

AU - Huang, Jing

AU - Dasgupta, Maupali

AU - Sears, Nathan

AU - Miyagi, Masaru

AU - Wang, Benlian

AU - Chance, Mark R.

AU - Chen, Xing

AU - Du, Yuping

AU - Wang, Yuxin

AU - An, Lizhe

AU - Wang, Qin

AU - Lu, Tao

AU - Zhang, Xiaodong

AU - Wang, Zhenghe

AU - Stark, George R.

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AB - Following its tyrosine phosphorylation, STAT3 is methylated on K140 by the histone methyl transferase SET9 and demethylated by LSD1 when it is bound to a subset of the promoters that it activates. Methylation of K140 is a negative regulatory event, because its blockade greatly increases the steady-state amount of activated STAT3 and the expression of many (i.e., SOCS3) but not all (i.e., CD14) STAT3 target genes. Biological relevance is shown by the observation that overexpression of SOCS3 when K140 cannot be methylated blocks the ability of cells to activate STAT3 in response to IL-6. K140 methylation does not occur with mutants of STAT3 that do not enter nuclei or bind to DNA. Following treatment with IL-6, events at the SOCS3 promoter occur in an ordered sequence, as shown by chromatin immunoprecipitations. Y705-phosphoryl- STAT3 binds first and S727 is then phosphorylated, followed by the coincident binding of SET9 and dimethylation of K140, and lastly by the binding of LSD1. We conclude that the lysine methylation of promoter-bound STAT3 leads to biologically important down-regulation of the dependent responses and that SET9, which is known to help provide an activating methylation mark to H3K4, is recruited to the newly activated SOCS3 promoter by STAT3.

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