TY - JOUR T1 - TET1 Modulates H4K16 Acetylation by Interacting with hMOF to Regulate Expression of DNA Repair Genes and Oncogenic Transformation JF - bioRxiv DO - 10.1101/024844 SP - 024844 AU - Jianing Zhong AU - Xianfeng Li AU - Wanshi Cai AU - Yan Wang AU - Shanshan Dong AU - Jian’an Zhang AU - Jie Yang AU - Kangli Wang AU - Fengbiao Mao AU - Cheng Zeng AU - Yuanyuan Li AU - Jinyu Wu AU - Huanming Yang AU - Xingzhi Xu AU - Zhong Sheng Sun Y1 - 2015/01/01 UR - http://biorxiv.org/content/early/2015/08/17/024844.abstract N2 - The Ten Eleven Translocation 1 (TET1) protein is a DNA demethylase that regulates gene expression through alteration of DNA methylation. Recent studies have demonstrated that TET1 could modulate transcriptional expression independent of its DNA demethylation activity; however, 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. Specifically, the TET1/SIN3A/hMOF complex mediates acetylation of histone H4 at lysine 16, via facilitating the binding of hMOF on chromatin, to regulate expression of important DNA repair genes in DNA double strand breaks, including TP53BP1, RAD50, RAD51, and BRCA1, for homologous recombination and non-homologous end joining repairs. Under hydrogen peroxide-induced DNA damage, dissociation of TET1 and hMOF from chromatin, concurrent with increased binding of SIRT1 on chromatin, led to hypo-acetylation of H4K16, reduced expression of these DNA repair genes, and DNA repair defects in a DNA methylation independent manner. A similar epigenetic dynamic alteration was also observed in H-RASV12 oncogenic-transformed cells, supporting the notion that suppression of TET1 downregulates DNA repair genes through modifying H4K16ac, instead of its demethylation function, and therefore contribute to tumorigenesis. Taken together, our results suggested a mechanistic link between a novel TET1 complex and H4K16ac, DNA repair genes expression, and genomic instability. ER -