title: TET1 modulates H4K16 acetylation by controlling auto-acetylation of hMOF to affect gene regulation and DNA repair function.
abstract: The Ten Eleven Translocation 1 (TET1) protein is a DNA demethylase that regulates gene expression through altering statue of DNA methylation. However, recent studies have demonstrated that TET1 could modulate transcriptional expression independent of its DNA demethylation activity; yet, the detailed mechanisms underlying TET1's role in such transcriptional regulation remain not well understood. Here, we uncovered that Tet1 formed a chromatin complex with histone acetyltransferase Mof and scaffold protein Sin3a in mouse embryonic stem cells by integrative genomic analysis using publicly available ChIP-seq data sets and a series of in vitro biochemical studies in human cell lines. Mechanistically, the TET1 facilitated chromatin affinity and enzymatic activity of hMOF against acetylation of histone H4 at lysine 16 via preventing auto-acetylation of hMOF, to regulate expression of the downstream genes, including DNA repair genes. We found that Tet1 knockout MEF cells exhibited an accumulation of DNA damage and genomic instability and Tet1 deficient mice were more sensitive to x-ray exposure. Taken together, our findings reveal that TET1 forms a complex with hMOF to modulate its function and the level of H4K16Ac ultimately affect gene expression and DNA repair.
authors.affiliation: Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325035, China.
authors.forename: Jianing
authors.initials: J
authors.lastname: Zhong
authors.affiliation: Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China.|University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Xianfeng
authors.initials: X
authors.lastname: Li
authors.affiliation: Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China.|University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Wanshi
authors.initials: W
authors.lastname: Cai
authors.affiliation: Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China.|University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325035, China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Dong
authors.affiliation: Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325035, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Yang
authors.affiliation: Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325035, China.
authors.forename: Jian'an
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325035, China.
authors.forename: Nana
authors.initials: N
authors.lastname: Wu
authors.affiliation: Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China.|University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China.|University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Fengbiao
authors.initials: F
authors.lastname: Mao
authors.affiliation: Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China.|University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Zeng
authors.affiliation: Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China.|University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Jinyu
authors.initials: J
authors.lastname: Wu
authors.affiliation: Beijing Key Laboratory of DNA Damage Response and College of Life Sciences, Capital Normal University, Beijing 100049, China.
authors.forename: Xingzhi
authors.initials: X
authors.lastname: Xu
authors.affiliation: Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325035, China sunzsbiols@126.com.|Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China.|University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Zhong Sheng
authors.initials: ZS
authors.lastname: Sun
mesh_terms: D000107:Acetylation; D000818:Animals; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D042822:Genomic Instability; D023281:Genomics / Q000379:methods; D059014:High-Throughput Nucleotide Sequencing; D051548:Histone Acetyltransferases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D000066450:Mouse Embryonic Stem Cells / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D056264:Sin3 Histone Deacetylase and Corepressor Complex
chemical_list: D004268:DNA-Binding Proteins; D006657:Histones; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C099683:SIN3A transcription factor; C540839:TET1 protein, mouse; D051548:Histone Acetyltransferases; D056264:Sin3 Histone Deacetylase and Corepressor Complex