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Reversible methylation of promoter-bound STAT3 by histone-modifying enzymes
Journal article   Open access   Peer reviewed

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, …
Proceedings of the National Academy of Sciences - PNAS, Vol.107(50), pp.21499-21504
12/14/2010
DOI: 10.1073/pnas.1016147107
PMCID: PMC3003019
PMID: 21098664
url
https://doi.org/10.1073/pnas.1016147107View
Published (Version of record) Open Access

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.
 Cell Line Promoter Regions, Genetic Histone-Lysine N-Methyltransferase - genetics Humans Suppressor of Cytokine Signaling Proteins - genetics Histone Demethylases - genetics Histone Demethylases - metabolism Suppressor of Cytokine Signaling 3 Protein Lysine - genetics Histones - genetics Histone-Lysine N-Methyltransferase - metabolism Lysine - metabolism Active Transport, Cell Nucleus Histones - metabolism Suppressor of Cytokine Signaling Proteins - metabolism Methylation Interleukin-6 - metabolism STAT3 Transcription Factor - genetics STAT3 Transcription Factor - metabolism

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