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Keywords:

  • gene regulation;
  • histone deacetylase;
  • post-translational modification;
  • SUMOylation;
  • transcription repressor

Abstract

Thumbnail image of graphical abstract

Methyl CpG binding protein 2 (MeCP2) binds to methylated DNA and acts as a transcriptional repressor. Mutations of human MECP2 gene lead to Rett syndrome, a severe neural developmental disorder. Here, we report that the MeCP2 protein can be modified by covalent linkage to small ubiquitin-like modifier (SUMO) and SUMOylation at lysine 223 is necessary for its transcriptional repression function. SUMOylation of MeCP2 is required for the recruitment of histone deacetylase complexes 1/2 complex. Mutation of MeCP2 lysine 223 to arginine abolishes its suppression of gene expression in mouse primary cortical neurons. Significantly, mutation of MeCP2 K223 site leads to developmental deficiency of rat hippocampal synapses in vitro and in vivo. Thus, the SUMOylation of MeCP2 at K223 is a critical switch for transcriptional repression and plays a crucial function in regulating synaptic development in the central nervous system.

The Methyl CpG binding protein 2 (MeCP2) is implicated in Rett syndrome and autism spectrum disorders. We showed that MeCP2 protein could be modified by SUMOylation and SUMOylation of MeCP2 is critical for its transcriptional regulation activity. Furthermore, we found that SUMOylation of MeCP2 plays a critical role in regulating synapse development in vitro and in vivo.