Becker, Annette ; Zhang, Peng ; Allmann, Lena ; Meilinger, Daniela ; Bertulat, Bianca ; Eck, Daniel ; Hofstaetter, Maria ; Bartolomei, Giody ; Hottiger, Michael ; Schreiber, Valerie ; Leonhardt, Heinrich ; Cardoso, M. Cristina (2016)
Poly(ADP-ribosyl)ation of Methyl CpG Binding Domain Protein 2 Regulates Chromatin Structure.
In: The Journal of biological chemistry, 291 (10)
Artikel, Bibliographie

Kurzbeschreibung (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.

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