Regulation of MECP2 expression and activity

Translation of MECP2 mRNA is negatively regulated by the microRNA miR-132. Transcription of miR-132 is regulated by BDNF signaling, through an unknown mechanism.

Binding of MECP2 to other proteins and to DNA is regulated by posttranslational modifications, of which phosphorylation has been best studied. Calcium dependent protein kinases, PKA and CaMK IV, activated by neuronal membrane depolarization, phosphorylate MECP2 at threonine residue T308 (corresponding to T320 in the longer MECP2 splicing isoform, MECP2_e1). Phosphorylation at T308 correlates with neuronal activity and inhibits binding of MECP2 to the nuclear receptor co-repressor complex (NCoR/SMRT). In resting neurons, MECP2 is phosphorylated at serine residue S80, which results in a decreased association of MECP2 with chromatin. Nuclear serine/threonine protein kinase HIPK2 phosphorylates MECP2 on serine residue S80. In activity-induced neurons, upon neuronal membrane depolarization, MECP2 S80 becomes dephosphorylated, and MECP2 acquires phosphorylation on serine S423 (corresponding to mouse Mecp2 serine S421). CaMK IV is one of the kinases that can phosphorylate MECP2 on S423. Phosphorylation of MECP2 at S423 increases MECP2 binding to chromatin. AURKB phosphorylates MECP2 at serine residue S423 in dividing adult neuronal progenitor cells.

Besides binding to the NCoR/SMRT co-repressor complex, MECP2 binds the SIN3A co-repressor complex. This interaction involves the transcriptional repressor domain of MECP2 and the amino terminal part of the HDAC interaction domain (HID) of SIN3A. HDAC1 and HDAC2 are part of the SIN3A co-repressor complex that co-immunoprecipitates with MECP2. While binding of MECP2 to SIN3A at target genes is associated with transcriptional repression, binding to CREB1 at target genes is associated with transcriptional activation. Function of MECP2 can be affected by binding to FOXG1, another gene mutated in Rett syndrome besides MECP2 and CDKL5, and HTT (Huntingtin). The subnuclear localization of MECP2 may be affected by binding to the Lamin B receptor (LBR).