title: Cooperative Action between SALL4A and TET Proteins in Stepwise Oxidation of 5-Methylcytosine.
abstract: TET family enzymes successively oxidize 5-methylcytosine to 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine, leading to eventual demethylation. 5hmC and TET enzymes occupy distinct chromatin regions, suggesting unknown mechanisms controlling the fate of 5hmC within diverse chromatin environments. Here, we report that SALL4A preferentially associates with 5hmC in vitro and occupies enhancers in mouse embryonic stem cells in a largely TET1-dependent manner. Although most 5hmC at SALL4A peaks undergoes further oxidation, this process is abrogated upon deletion of Sall4 gene, with a concomitant reduction of TET2 at these regions. Thus, SALL4A facilitates further oxidation of 5hmC at its binding sites, which requires its 5hmC-binding activity and TET2, supporting a collaborative action between SALL4A and TET proteins in regulating stepwise oxidation of 5mC at enhancers. Our study identifies SALL4A as a 5hmC binder, which facilitates 5hmC oxidation by stabilizing TET2 association, thereby fine-tuning expression profiles of developmental genes in mouse embryonic stem cells.
authors.affiliation: National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Xiong
authors.affiliation: National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China. Electronic address: zhangzhuqiang@ibp.ac.cn.
authors.forename: Zhuqiang
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Clinical and Translational Research Center of Shanghai First Maternity & Infant Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
authors.forename: Jiayu
authors.initials: J
authors.lastname: Chen
authors.affiliation: The State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Huang
authors.affiliation: National Institute of Biological Sciences, Beijing 102206, China.
authors.forename: Yali
authors.initials: Y
authors.lastname: Xu
authors.affiliation: National Institute of Biological Sciences, Beijing 102206, China.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Ding
authors.affiliation: National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Kidney Development, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Nishinakamura
authors.affiliation: The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Guo-Liang
authors.initials: GL
authors.lastname: Xu
authors.affiliation: The State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.
authors.forename: Hailin
authors.initials: H
authors.lastname: Wang
authors.affiliation: National Institute of Biological Sciences, Beijing 102206, China.
authors.forename: She
authors.initials: S
authors.lastname: Chen
authors.affiliation: Clinical and Translational Research Center of Shanghai First Maternity & Infant Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
authors.forename: Shaorong
authors.initials: S
authors.lastname: Gao
authors.affiliation: National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: zhubing@ibp.ac.cn.
authors.forename: Bing
authors.initials: B
authors.lastname: Zhu
mesh_terms: D044503:5-Methylcytosine / Q000378:metabolism*; D000818:Animals; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D049308:Dioxygenases; D053595:Embryonic Stem Cells / Q000378:metabolism*; D004742:Enhancer Elements, Genetic / Q000502:physiology; D051379:Mice; D010084:Oxidation-Reduction; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C509167:Sall4 protein, mouse; C540839:TET1 protein, mouse; D014157:Transcription Factors; D044503:5-Methylcytosine; D049308:Dioxygenases; C551914:Tet2 protein, mouse
keywords: DNA methylation; SALL4; TET1; TET2; enhancer; oxidation