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

TLDR

Mutations in MeCP2 cause Rett syndrome, and both loss‑of‑function and over‑expression lead to various neuropsychiatric disorders. The study examined hypothalamic gene expression in mice lacking or overexpressing MeCP2 to uncover mechanisms of these disorders. They profiled hypothalamic transcriptomes in MeCP2‑deficient and MeCP2‑overexpressing mice and validated MeCP2 binding to promoters of six selected genes. MeCP2 dysfunction altered thousands of genes, with ~85% activated, and its association with CREB1 at activated promoters indicates it can act as both an activator and repressor of 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 the 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 unexpectedly the majority of genes (approximately 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 a repressor of transcription.