Binding of MECP2 to the promoter of the BDNF gene represses BDNF transcription in unstimulated neurons, tying BDNF expression with neuronal membrane depolarization (Chen et al. 2003, Martinowich et al. 2003). BDNF encodes Brain-derived neurotrophic factor. MECP2-mediated recruitment of the histone deacetylase (HDAC) containing SIN3A co-repressor complex is thought to induce histone deacetylation at the BDNF promoter, invoking BDNF gene silencing (Martinowich et al. 2003).
Surprisingly, MECP2 deficiency in Rett syndrome results in an overall decreased expression of BDNF (Klein et al. 2007, Chahrour et al. 2008, Fyffe et al. 2008). One proposed mechanism is indirect, through the loss of MECP2-mediated repression of REST and RCOR1 (CoREST) genes, as REST and RCOR1 act as repressors of BDNF transcription from promoter 1 (Abuhatzira et al. 2007). Previously, it was reported that the CoREST complex also represses transcription of Bdnf from the Mecp2-binding murine promoter 4 (corresponding to human MECP2-binding BDNF promoter 3) (Ballas et al. 2005).
For detailed review of dual regulation of BDNF transcription by MECP2, please refer to Li and Pozzo-Miller 2014, and KhorashidAhmad et al. 2016.
Deficit in Bdnf expression in Mecp2 null mice results in downregulation of Igf1 expression through a microRNA-dependent pathway regulated by Bdnf signaling. Induction of signaling by the beta2-adrenegic receptor can restore Igf1 expression in Mecp2 null mice (Mellios et al. 2014).