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Poly(ADP-ribosyl)ation of Methyl CpG Binding Domain Protein 2 Regulates Chromatin Structure.

Becker, Annette and Zhang, Peng and Allmann, Lena and Meilinger, Daniela and Bertulat, Bianca and Eck, Daniel and Hofstaetter, Maria and Bartolomei, Giody and Hottiger, Michael and Schreiber, Valerie and Leonhardt, Heinrich and Cardoso, M. Cristina (2016):
Poly(ADP-ribosyl)ation of Methyl CpG Binding Domain Protein 2 Regulates Chromatin Structure.
In: The Journal of biological chemistry, pp. 4873-4881, 291, (10), ISSN 1083-351X, [Article]

Abstract

The epigenetic information encoded in the genomic DNA methylation pattern is translated by methyl-cytosine binding proteins like MeCP2 into chromatin topology and structure and gene activity states. We have previously shown that MeCP2 level increases during differentiation and causes large-scale chromatin reorganization, which is disturbed by MeCP2 Rett syndrome mutations. Phosphorylation and other post-translational modifications of MeCP2 have been recently described to modulate its function. Here, we show poly(ADP-ribosyl)ation of endogenous MeCP2 in mouse brain tissue. Consequently, we find that MeCP2 induced aggregation of pericentric heterochromatin and its chromatin accumulation was enhanced in PARP-1-/- compared to 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 chromatin large scale remodeling. Single or double deletion of the poly(ADP-ribosyl)ated regions as well as 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 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.

Item Type: Article
Erschienen: 2016
Creators: Becker, Annette and Zhang, Peng and Allmann, Lena and Meilinger, Daniela and Bertulat, Bianca and Eck, Daniel and Hofstaetter, Maria and Bartolomei, Giody and Hottiger, Michael and Schreiber, Valerie and Leonhardt, Heinrich and Cardoso, M. Cristina
Title: Poly(ADP-ribosyl)ation of Methyl CpG Binding Domain Protein 2 Regulates Chromatin Structure.
Language: English
Abstract:

The epigenetic information encoded in the genomic DNA methylation pattern is translated by methyl-cytosine binding proteins like MeCP2 into chromatin topology and structure and gene activity states. We have previously shown that MeCP2 level increases during differentiation and causes large-scale chromatin reorganization, which is disturbed by MeCP2 Rett syndrome mutations. Phosphorylation and other post-translational modifications of MeCP2 have been recently described to modulate its function. Here, we show poly(ADP-ribosyl)ation of endogenous MeCP2 in mouse brain tissue. Consequently, we find that MeCP2 induced aggregation of pericentric heterochromatin and its chromatin accumulation was enhanced in PARP-1-/- compared to 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 chromatin large scale remodeling. Single or double deletion of the poly(ADP-ribosyl)ated regions as well as 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 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.

Journal or Publication Title: The Journal of biological chemistry
Volume: 291
Number: 10
Divisions: 10 Department of Biology
10 Department of Biology > Cell Biology and Epigenetics
Date Deposited: 28 Jan 2016 06:59
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