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Poly(ADP-ribosyl)ation of Methyl CpG binding domain protein 2 regulates chromatin structure

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Item Type:Article
Title:Poly(ADP-ribosyl)ation of Methyl CpG binding domain protein 2 regulates chromatin structure
Creators Name:Becker, A. and Zhang, P. and Allmann, L. and Meilinger, D. and Bertulat, B. and Eck, D. and Hofstaetter, M. and Bartolomei, G. and Hottiger, M.O. and Schreiber, V. and Leonhardt, H. and Cardoso, M.C.
Abstract:The epigenetic information encoded in the genomic DNA methylation pattern is translated by methylcytosine binding proteins like MeCP2 into chromatin topology and structure and gene activity states. We have shown previously that the MeCP2 level increases during differentiation and that it causes large-scale chromatin reorganization, which is disturbed by MeCP2 Rett syndrome mutations. Phosphorylation and other posttranslational modifications of MeCP2 have been described recently to modulate its function. Here we show poly(ADP-ribosyl)ation of endogenous MeCP2 in mouse brain tissue. Consequently, we found that MeCP2 induced aggregation of pericentric heterochromatin and that its chromatin accumulation was enhanced in poly(ADP-ribose) polymerase (PARP) 1(-/-) compared with wild-type cells. We mapped the poly(ADP-ribosyl)ation domains and engineered MeCP2 mutation constructs to further analyze potential effects on DNA binding affinity and large-scale chromatin remodeling. Single or double deletion of the poly(ADP-ribosyl)ated regions and PARP inhibition increased the heterochromatin clustering ability of MeCP2. Increased chromatin clustering may reflect increased binding affinity. In agreement with this hypothesis, we found that PARP-1 deficiency significantly increased the chromatin binding affinity of MeCP2 in vivo. These data provide novel mechanistic insights into the regulation of MeCP2-mediated, higher-order chromatin architecture and suggest therapeutic opportunities to manipulate MeCP2 function.
Keywords:5-Methylcytosine, Chromatin Remodeling, DNA Methylation, Heterochromatin, Post-Translational Modification (PTM), MeCP2, PARP-1, Chromatin Binding and Organization, Poly(ADP-ribosyl)ation, Animals, Mice, Rats, Spodoptera
Source:Journal of Biological Chemistry
Publisher:American Society for Biochemistry and Molecular Biology
Page Range:4873-4881
Date:4 March 2016
Official Publication:https://doi.org/10.1074/jbc.M115.698357
PubMed:View item in PubMed

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