title: Reversible methylation of promoter-bound STAT3 by histone-modifying enzymes.
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.
authors.affiliation: School of Life Science, Lanzhou University, Lanzhou, Gansu 73000, People's Republic of China. yangjb@lzu.edu.cn
authors.forename: Jinbo
authors.initials: J
authors.lastname: Yang
authors.forename: Jing
authors.initials: J
authors.lastname: Huang
authors.forename: Maupali
authors.initials: M
authors.lastname: Dasgupta
authors.forename: Nathan
authors.initials: N
authors.lastname: Sears
authors.forename: Masaru
authors.initials: M
authors.lastname: Miyagi
authors.forename: Benlian
authors.initials: B
authors.lastname: Wang
authors.forename: Mark R
authors.initials: MR
authors.lastname: Chance
authors.forename: Xing
authors.initials: X
authors.lastname: Chen
authors.forename: Yuping
authors.initials: Y
authors.lastname: Du
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Wang
authors.forename: Lizhe
authors.initials: L
authors.lastname: An
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
authors.forename: Tao
authors.initials: T
authors.lastname: Lu
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zhang
authors.forename: Zhenghe
authors.initials: Z
authors.lastname: Wang
authors.forename: George R
authors.initials: GR
authors.lastname: Stark
mesh_terms: D021581:Active Transport, Cell Nucleus; D002460:Cell Line; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D008745:Methylation; D011401:Promoter Regions, Genetic; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D006657:Histones; D015850:Interleukin-6; C106644:SOCS3 protein, human; D050796:STAT3 Transcription Factor; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D056466:Histone Demethylases; C495195:KDM1A protein, human; D011495:Histone-Lysine N-Methyltransferase; C540312:SETD7 protein, human; D008239:Lysine