Disruptions in the expression of the BDNF gene that encodes a neurotrophic factor involved in neuronal survival, differentiation and synaptic plasticity has been proposed to contribute to the molecular pathogenesis of Rett syndrome. Rett syndrome (RTT) is a neurodevelopmental disorder, caused by mutations in the X-linked methyl CpG binding protein 2 gene (MeCP2). MeCP2 deficiency in the brain has been shown to decrease overall expression of BDNF in spite of an observed increase in the activity of promoter III that appears to be controlled directly by MeCP2. Therefore, how MeCP2 deficiency causes an overall downregulation of BDNF expression was an enigma. Here we report that MeCP2 deficiency in human and mouse brain causes an increase in expression of two neuronal gene transcriptional repressors REST (RE1 silencing transcription factor), and CoREST. MeCP2 binds to and is involved in repression of Rest and CoRest promoters despite their unmethylated state. MeCP2 depletion is associated with a change in the histone modification profile to a more active conformation. The elevated levels of REST and CoREST in the brain of RTT patients and MeCP2 deficient mice result in downregulation of BDNF, apparently by their binding to the REI (element) located between the first two promoters of the BDNF gene. Interestingly, the NTRK2 gene that encodes the BDNF receptor, TRKB, was overexpressed in MeCP2 deficient human and mouse brains either directly or as an attempt to compensate for BDNF deficiency.
Bibliographical noteFunding Information:
We thank Howard Cedar for his thoughtful reading of the manuscript and for his invaluable suggestions. This work was supported by grants from the Rett Syndrome Research Foundations in USA and Israel, the Israel Science Foundation, and March of Dimes Birth Defects Foundation for Inborn Disease in the USA.
- BDNF regulation
- DNA methylation
- Histone modifications
- MeCP2 deficiency
- REST/CoREST expression