title: Specific phosphorylation of histone demethylase KDM3A determines target gene expression in response to heat shock.
abstract: Histone lysine (K) residues, which are modified by methyl- and acetyl-transferases, diversely regulate RNA synthesis. Unlike the ubiquitously activating effect of histone K acetylation, the effects of histone K methylation vary with the number of methyl groups added and with the position of these groups in the histone tails. Histone K demethylases (KDMs) counteract the activity of methyl-transferases and remove methyl group(s) from specific K residues in histones. KDM3A (also known as JHDM2A or JMJD1A) is an H3K9me2/1 demethylase. KDM3A performs diverse functions via the regulation of its associated genes, which are involved in spermatogenesis, metabolism, and cell differentiation. However, the mechanism by which the activity of KDM3A is regulated is largely unknown. Here, we demonstrated that mitogen- and stress-activated protein kinase 1 (MSK1) specifically phosphorylates KDM3A at Ser264 (p-KDM3A), which is enriched in the regulatory regions of gene loci in the human genome. p-KDM3A directly interacts with and is recruited by the transcription factor Stat1 to activate p-KDM3A target genes under heat shock conditions. The demethylation of H3K9me2 at the Stat1 binding site specifically depends on the co-expression of p-KDM3A in the heat-shocked cells. In contrast to heat shock, IFN-γ treatment does not phosphorylate KDM3A via MSK1, thereby abrogating its downstream effects. To our knowledge, this is the first evidence that a KDM can be modified via phosphorylation to determine its specific binding to target genes in response to thermal stress.
authors.affiliation: State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, China.
authors.forename: Mo-bin
authors.initials: MB
authors.lastname: Cheng
authors.affiliation: State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, China.
authors.forename: Chun-yu
authors.initials: CY
authors.lastname: Cao
authors.affiliation: Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Wei-long
authors.initials: WL
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, China.
authors.forename: Yu-fei
authors.initials: YF
authors.lastname: Shen
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D015894:Genome, Human; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D018869:Heat-Shock Response / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D056484:Jumonji Domain-Containing Histone Demethylases / Q000737:chemistry / Q000378:metabolism*; D019169:Jurkat Cells; D008954:Models, Biological; D008969:Molecular Sequence Data; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013312:Stress, Physiological / Q000187:drug effects / Q000235:genetics
chemical_list: D018841:HSP90 Heat-Shock Proteins; D050794:STAT1 Transcription Factor; D010768:Phosphoserine; D007371:Interferon-gamma; D056484:Jumonji Domain-Containing Histone Demethylases; C530247:KDM3A protein, human; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1