Dataset Information

Interaction with the DNA Repair Protein Thymine DNA Glycosylase Regulates Histone Acetylation by p300.

ABSTRACT: How protein-protein interactions regulate and alter histone modifications is a major unanswered question in epigenetics. The histone acetyltransferase p300 binds thymine DNA glycosylase (TDG); utilizing mass spectrometry to measure site-specific changes in histone acetylation, we found that the absence of TDG in mouse embryonic fibroblasts leads to a reduction in the rate of histone acetylation. We demonstrate that TDG interacts with the CH3 domain of p300 to allosterically promote p300 activity to specific lysines on histone H3 (K18 and K23). However, when TDG concentrations approach those of histones, TDG acts as a competitive inhibitor of p300 histone acetylation. These results suggest a mechanism for how histone acetylation is fine-tuned via interaction with other proteins, while also highlighting a connection between regulators of two important biological processes: histone acetylation and DNA repair/demethylation.

SUBMITTER: Henry RA

PROVIDER: S-EPMC5206798 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Interaction with the DNA Repair Protein Thymine DNA Glycosylase Regulates Histone Acetylation by p300.

Henry Ryan A RA Mancuso Pietro P Kuo Yin-Ming YM Tricarico Rossella R Tini Marc M Cole Philip A PA Bellacosa Alfonso A Andrews Andrew J AJ

Biochemistry 20161201 49

How protein-protein interactions regulate and alter histone modifications is a major unanswered question in epigenetics. The histone acetyltransferase p300 binds thymine DNA glycosylase (TDG); utilizing mass spectrometry to measure site-specific changes in histone acetylation, we found that the absence of TDG in mouse embryonic fibroblasts leads to a reduction in the rate of histone acetylation. We demonstrate that TDG interacts with the CH3 domain of p300 to allosterically promote p300 activity ...[more]

PMID: 27951654

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Project description:BackgroundDNA methylation is one way to encode epigenetic information and plays a crucial role in regulating gene expression during embryonic development. DNA methylation marks are established by the DNA methyltransferases and, recently, a mechanism for active DNA demethylation has emerged involving the ten-eleven translocator proteins and thymine DNA glycosylase (TDG). However, so far it is not clear how these enzymes are recruited to, and regulate DNA methylation at, specific genomic loci. A number of studies imply that sequence-specific transcription factors are involved in targeting DNA methylation and demethylation processes. Oestrogen receptor beta (ERβ) is a ligand-inducible transcription factor regulating gene expression in response to the female sex hormone oestrogen. Previously, we found that ERβ deficiency results in changes in DNA methylation patterns at two gene promoters, implicating an involvement of ERβ in DNA methylation. In this study, we set out to explore this involvement on a genome-wide level, and to investigate the underlying mechanisms of this function.ResultsUsing reduced representation bisulfite sequencing, we compared genome-wide DNA methylation in mouse embryonic fibroblasts derived from wildtype and ERβ knock-out mice, and identified around 8000 differentially methylated positions (DMPs). Validation and further characterisation of selected DMPs showed that differences in methylation correlated with changes in expression of the nearest gene. Additionally, re-introduction of ERβ into the knock-out cells could reverse hypermethylation and reactivate expression of some of the genes. We also show that ERβ is recruited to regions around hypermethylated DMPs. Finally, we demonstrate here that ERβ interacts with TDG and that TDG binds ERβ-dependently to hypermethylated DMPs.ConclusionWe provide evidence that ERβ plays a role in regulating DNA methylation at specific genomic loci, likely as the result of its interaction with TDG at these regions. Our findings imply a novel function of ERβ, beyond direct transcriptional control, in regulating DNA methylation at target genes. Further, they shed light on the question how DNA methylation is regulated at specific genomic loci by supporting a concept in which sequence-specific transcription factors can target factors that regulate DNA methylation patterns.

Dataset Information

Interaction with the DNA Repair Protein Thymine DNA Glycosylase Regulates Histone Acetylation by p300.

Publications

Interaction with the DNA Repair Protein Thymine DNA Glycosylase Regulates Histone Acetylation by p300.

Similar Datasets

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