Updated project metadata.
Rett syndrome is a human intellectual disability disorder that is associated with mutations in the X-linked MECP2 gene. The
epigenetic reader MeCP2 binds to methylated cytosines on the DNA and regulates chromatin organization. We have shown
previously that MECP2 Rett syndrome missense mutations are impaired in chromatin binding and heterochromatin
reorganization. Here, we performed a proteomics analysis of post-translational modifications of MeCP2 isolated from adult mouse
brain. We show that MeCP2 carries various post-translational modifications, among them phosphorylation on S80 and S421, which
lead to minor changes in either heterochromatin binding kinetics or clustering. We found that MeCP2 is (di)methylated on several
arginines and that this modification alters heterochromatin organization. Interestingly, we identified the Rett syndrome mutation
site R106 as a dimethylation site. In addition, co-expression of protein arginine methyltransferases 1 and 6 lead to a decrease of
heterochromatin clustering. Altogether, we identified and validated novel modifications of MeCP2 in the brain and show that these
can modulate its ability to bind as well as reorganize heterochromatin, which may play a role in the pathology of Rett syndrome.