MeCP2 Represses the Rate of Transcriptional Initiation of Highly Methylated Long Genes

• Published in: Molecular cell Vol. 77; no. 2; pp. 294 - 309.e9
• Main Authors: Boxer, Lisa D., Renthal, William, Greben, Alexander W., Whitwam, Tess, Silberfeld, Andrew, Stroud, Hume, Li, Emmy, Yang, Marty G., Kinde, Benyam, Griffith, Eric C., Bonev, Boyan, Greenberg, Michael E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16.01.2020
• Subjects: Animals; Brain - physiology; DNA - genetics; DNA methylation; DNA Methylation - genetics; Male; MeCP2; Methyl-CpG-Binding Protein 2 - genetics; Mice; Mice, Knockout; Mutation - genetics; NCoR; Neurons - physiology; Repressor Proteins - genetics; Rett syndrome; Rett Syndrome - genetics; RNA - genetics; RNA Pol II; Transcription, Genetic - genetics; transcriptional elongation; transcriptional initiation; MeCP2; transcriptional elongation; transcriptional initiation; Rett syndrome; DNA methylation; RNA Pol II; NCoR
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2019.10.032

Mutations in the methyl-DNA-binding repressor protein MeCP2 cause the devastating neurodevelopmental disorder Rett syndrome. It has been challenging to understand how MeCP2 regulates transcription because MeCP2 binds broadly across the genome and MeCP2 mutations are associated with widespread small-magnitude changes in neuronal gene expression. We demonstrate here that MeCP2 represses nascent RNA transcription of highly methylated long genes in the brain through its interaction with the NCoR co-repressor complex. By measuring the rates of transcriptional initiation and elongation directly in the brain, we find that MeCP2 has no measurable effect on transcriptional elongation, but instead represses the rate at which Pol II initiates transcription of highly methylated long genes. These findings suggest a new model of MeCP2 function in which MeCP2 binds broadly across highly methylated regions of DNA, but acts at transcription start sites to attenuate transcriptional initiation. [Display omitted] •MeCP2 represses transcription of highly methylated long genes through NCoR•Direct measurements of transcriptional initiation and elongation rates in the mouse brain•MeCP2 reduces transcriptional initiation, not elongation, of highly methylated long genes•Gene body-TSS contacts position distal MeCP2 molecules at the TSS Mutations in MeCP2 cause the neurodevelopmental disorder Rett syndrome. Although MeCP2 binding is enriched in methylated gene bodies, Boxer et al. find that MeCP2 decreases the rate of transcriptional initiation, but not elongation, of highly methylated long genes in the brain through its interaction with the NCoR co-repressor complex.