A Novel TET1 Based Complex Controls DNA Repair Genes by Modulating H4K16 Acetylation In response to oxidative damage [RRBS]

TET1, in addition its function as a DNA demethylase, plays important roles in both transcriptional repression and activation. However, the underlying mechanism how TET1 functions in transcriptional regulation remains elusive. Here, by integrative genomic and biochemical studies, we demonstrate that TET1 forms a novel chromatin modifying complex with hMOF, SIRT1, and the scaffold protein SIN3A to specifically regulate DNA repair genes by modulating H4K16 acetylation. Dynamic recomposition of this complex induced by oxidative damage, characterized as dissociation of TET1 and hMOF or increased binding of SIRT1, leads to hypoacetylation of H4K16 to repress the expression of DNA repair genes. Importantly, similar recomposition of this complex was validated in an oncogenic transformation cell line, which further endorsed that the role of this complex was involved in tumorigenesis. Our findings reveal a novel mechanism for TET1 to modulate H4K16ac by chromatin recomposition, with which TET1 regulates the expression of DNA repair genes instead of its well-known role in DNA demethylation. Overall design: Reduced representation bisulfite sequencing (MspI,~40-220bp size fraction) data for HEK293T cell line with or without H2O2 treatment were generated by deep sequencing, using Illumina Illumina HiSeq 2000.