MeCP2, a Key Contributor to Neurological Disease, Activates and Represses Transcription

Abstract

Mutations in the gene encoding the transcriptional repressor methyl-CpG binding protein 2 (MeCP2) cause the neurodevelopmental disorder Rett syndrome. Loss of function as well as increased dosage of MECP2 gene cause a host of neuropsychiatric disorders. To explore the molecular mechanism(s) underlying these disorders, we examined gene expression patterns in the hypothalamus of mice that either lack or overexpress MeCP2. In both models, MeCP2 dysfunction induced changes in the expression levels of thousands of genes, but surprisingly the majority of genes (~85%) appeared to be activated by MeCP2. We selected six genes and confirmed that MeCP2 binds to their promoters. Furthermore, we showed that MeCP2 associates with the transcriptional activator CREB1 at the promoter of an activated target but not a repressed target. These studies suggest that MeCP2 regulates the expression of a wide range of genes in the hypothalamus and that it can function as both an activator and repressor of transcription.Rett syndrome (RTT, MIM 312750) is a progressive neurodevelopmental disorder caused by mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2) (1). RTT patients appear to develop normally up to the first year of age after which they lose any acquired speech and replace purposeful hand use with stereotypies. MECP2 mutations also result in a host of neurobehavioral abnormalities, ranging from mild learning disabilities to autism, Xlinked mental retardation, and infantile encephalopathy. Interestingly, an increase in MECP2 dosage is equally detrimental to the nervous system: duplications spanning the MECP2 locus cause features overlapping with those of RTT and related neurological disorders (2).

Essential Role of MeCP2 in the Regulation of Myofibroblast Differentiation during Pulmonary Fibrosis

“…23,24 These studies implicate a role for the methyl CpG binding protein 2 (MeCP2), a key member of the methyl-DNA binding protein family of proteins. [25][26][27][28][29] While MeCP2 can bind to unmethylated DNA, 29 preferentially it binds methylated DNA at the 5=-CpG residues. 30 -31 MeCP2 is originally considered to be a transcriptional repressor in conjunction with Sin3A and histone deacetylase, but was found later to also have a significant role as a transcriptional activator, as well as in the regulation of chromatin architecture and RNA splicing.…”

“…27 Since methylated DNA residues are present in the ␣-SMA gene 19 4 sibility of MeCP2 binding to these ␣-SMA gene sequences was initially investigated by incubation of recombinant MeCP2 with methylated and unmethylated DNA probes containing the sequences corresponding to the 3 CpG islands present in the ␣-SMA gene. They were then analyzed on nondenaturing polyacrylamide gels in an electrophoretic mobility shift assay.…”

Discovery of Rare Mutations in Autism: Elucidating Neurodevelopmental Mechanisms

“…When MeCP2 is bound to chromatin, the transcriptional repressor domain interacts with histone deacetylases, resulting in transcriptional repression of target genes containing CpG residues [71]. More recent evidence also supports the role of MeCP2 in gene activation [75].…”

DNA methylation in fibrosis

“…MeCP2-null mice had around ~85% of dysregulated genes in their hypothalamus downregulated (2184 out of the 2582 genes). At the site of activated gene promoters, MeCP2 is associated with CREB1, a transcriptional activator (Chahrour et al, 2008).…”