MeCP2 and Major Satellite Forward RNA Cooperate for Pericentric Heterochromatin Organization

Methyl-CpG binding protein 2 (MeCP2) has historically been linked to heterochromatin organization, and in mouse cells it accumulates at pericentric heterochromatin (PCH), closely following major satellite (MajSat) DNA distribution. However, little is known about the specific function of MeCP2 in these regions. We describe the first evidence of a role in neurons for MeCP2 and MajSat forward (MajSat-fw) RNA in reciprocal targeting to PCH through their physical interaction. Moreover, MeCP2 contributes to maintenance of PCH by promoting deposition of H3K9me3 and H4K20me3. We highlight that the MeCP2B isoform is required for correct higher-order PCH organization, and underline involvement of the methyl-binding and transcriptional repression domains. The T158 residue, which is commonly mutated in Rett patients, is directly involved in this process. Our findings support the hypothesis that MeCP2 and the MajSat-fw transcript are mutually dependent for PCH organization, and contribute to clarify MeCP2 function in the regulation of chromatin architecture. [Display omitted] •MeCP2 and MajSat-fw transcript targeting to chromocenters is mutually dependent•MeCP2B and its MBD domain are required for correct higher-order PCH organization•The TRD domain of the MeCP2 protein binds the MajSat-fw transcript•The Rett syndrome T158M mutation of MeCP2 impairs higher-order PCH organization Della Ragione and colleagues describe a novel function of MeCP2 and MajSat forward transcript in terms of their reciprocal targeting to chromocenters in neurons through their physical interaction. Moreover, MeCP2B has a prominent role in higher-order PCH organization, with both its MBD and TRD involved in this process. These findings further clarify MeCP2 function in the regulation of chromatin architecture.