title: Cross talk between histone deacetylase 4 and STAT6 in the transcriptional regulation of arginase 1 during mouse dendritic cell differentiation.
abstract: l-Arginine and l-arginine-metabolizing enzymes play important roles in the biology of some types of myeloid cells, including macrophage and myeloid-derived suppressor cells. In this study, we found evidence that arginase 1 (Arg1) is required for the differentiation of mouse dendritic cells (DCs). Expression of Arg1 was robustly induced during monocyte-derived DC differentiation. Ectopic expression of Arg1 significantly promoted monocytic DC differentiation in a granulocyte-macrophage colony-stimulating factor culture system and also facilitated the differentiation of CD8α(+) conventional DCs in the presence of Flt3 ligand. Knockdown of Arg1 reversed these effects. Mechanistic studies showed that the induced expression of Arg1 in differentiating DCs was caused by enhanced recruitment of histone deacetylase 4 (HDAC4) to the Arg1 promoter region, which led to a reduction in the acetylation of both the histone 3 and STAT6 proteins and subsequent transcriptional activation of Arg1. Further investigation identified a novel STAT6 binding site within the Arg1 promoter that mediated its regulation by STAT6 and HDAC4. These observations suggest that the cross talk between HDAC4 and STAT6 is an important regulatory mechanism of Arg1 transcription in DCs. Moreover, overexpression of Arg1 clearly abrogated the ability of HDAC inhibitors to suppress DC differentiation. In conclusion, we show that Arg1 is a novel regulator of myeloid DC differentiation.
authors.affiliation: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Jianyang
authors.initials: J
authors.lastname: Wei
authors.affiliation: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Limei
authors.initials: L
authors.lastname: Zhong
authors.affiliation: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Maohua
authors.initials: M
authors.lastname: Shi
authors.affiliation: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Pan
authors.initials: P
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Shengkai
authors.initials: S
authors.lastname: Zuo
authors.affiliation: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Kang
authors.initials: K
authors.lastname: Wu
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Mingjiang
authors.initials: M
authors.lastname: Zhu
authors.affiliation: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Chinese Ministry of Education, Guangzhou, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Huang
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Chinese Ministry of Education, Guangzhou, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Huiyong
authors.initials: H
authors.lastname: Yin
authors.affiliation: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Chinese Ministry of Education, Guangzhou, China zhouj72@mail.sysu.edu.cn.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
mesh_terms: D000818:Animals; D001119:Arginase / Q000378:metabolism*; D001665:Binding Sites; D016827:CD8 Antigens / Q000378:metabolism; D002454:Cell Differentiation; D002469:Cell Separation; D003713:Dendritic Cells / Q000166:cytology*; D015971:Gene Expression Regulation, Enzymologic; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D057809:HEK293 Cells; D006655:Histone Deacetylases / Q000502:physiology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009000:Monocytes / Q000166:cytology; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000502:physiology; D050800:STAT6 Transcription Factor / Q000502:physiology*
chemical_list: D016827:CD8 Antigens; D006657:Histones; D012097:Repressor Proteins; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; C494100:Stat6 protein, mouse; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C400300:HDAC4 protein, human; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases; C544448:Arg1 protein, mouse; D001119:Arginase