title: HDAC4 mediates IFN-γ induced disruption of energy expenditure-related gene expression by repressing SIRT1 transcription in skeletal muscle cells.
abstract: Metabolic homeostasis is achieved through balanced energy storage and output. Impairment of energy expenditure is a hallmark event in patients with obesity and type 2 diabetes. Previously we have shown that the pro-inflammatory cytokine interferon gamma (IFN-γ) disrupts energy expenditure in skeletal muscle cells via hypermethylated in cancer 1 (HIC1)-class II transactivator (CIITA) dependent repression of SIRT1 transcription. Here we report that repression of SIRT1 transcription by IFN-γ paralleled loss of histone acetylation on the SIRT1 promoter region with simultaneous recruitment of histone deacetylase 4 (HDAC4). IFN-γ activated HDAC4 in vitro and in vivo by up-regulating its expression and stimulating its nuclear accumulation. HIC1 and CIITA recruited HDAC4 to the SIRT1 promoter and cooperated with HDAC4 to repress SIRT1 transcription. HDAC4 depletion by small interfering RNA or pharmaceutical inhibition normalized histone acetylation on the SIRT1 promoter and restored SIRT1 expression in the presence of IFN-γ. Over-expression of HDAC4 suppressed the transcription of genes involved in energy expenditure in a SIRT1-dependent manner. In contrast, HDAC4 knockdown/inhibition neutralized the effect of IFN-γ on cellular metabolism by normalizing SIRT1 expression. Therefore, our data reveal a role for HDAC4 in regulating cellular energy output and as such provide insights into rationalized design of novel anti-diabetic therapeutics.
authors.affiliation: Key Laboratory of Cardiovascular Disease, Department of Pathophysiology, Nanjing Medical University, Nanjing, China; Department of Nursing, Jiangsu Jiankang Vocational University, Nanjing, China.
authors.forename: Mingming
authors.initials: M
authors.lastname: Fang
authors.affiliation: Key Laboratory of Cardiovascular Disease, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
authors.forename: Zhiwen
authors.initials: Z
authors.lastname: Fan
authors.affiliation: Key Laboratory of Cardiovascular Disease, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
authors.forename: Wenfang
authors.initials: W
authors.lastname: Tian
authors.affiliation: Key Laboratory of Cardiovascular Disease, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
authors.forename: Yuhao
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Cardiovascular Disease, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.affiliation: Key Laboratory of Cardiovascular Disease, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
authors.forename: Huihui
authors.initials: H
authors.lastname: Xu
authors.affiliation: Key Laboratory of Cardiovascular Disease, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
authors.forename: Bisheng
authors.initials: B
authors.lastname: Zhou
authors.affiliation: Department of Biochemistry, Xinjiang Medical University, Urumqi, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Cardiovascular Disease, Department of Pathophysiology, Nanjing Medical University, Nanjing, China. Electronic address: wxy@njmu.edu.cn.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wu
authors.affiliation: Key Laboratory of Cardiovascular Disease, Department of Pathophysiology, Nanjing Medical University, Nanjing, China. Electronic address: yxu2005@gmail.com.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
mesh_terms: D000107:Acetylation; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004734:Energy Metabolism / Q000235:genetics; D005786:Gene Expression Regulation; D006655:Histone Deacetylases / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics* / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics; D009765:Obesity / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics*; D056564:Sirtuin 1 / Q000096:biosynthesis / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics; D014158:Transcription, Genetic; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: C499808:HIC1 protein, human; D051741:Kruppel-Like Transcription Factors; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D007371:Interferon-gamma; C447939:SIRT1 protein, human; D056564:Sirtuin 1; C400300:HDAC4 protein, human; D006655:Histone Deacetylases
keywords: CIITA; Epigenetics; HDAC4; IFN-γ; Transcriptional regulation