@article{382ed37637e7451f8e323c467a65c420,
title = "MeCP2 Represses the Rate of Transcriptional Initiation of Highly Methylated Long Genes",
abstract = "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.",
keywords = "DNA methylation, MeCP2, NCoR, RNA Pol II, Rett syndrome, transcriptional elongation, transcriptional initiation",
author = "Boxer, {Lisa D.} and William Renthal and Greben, {Alexander W.} and Tess Whitwam and Andrew Silberfeld and Hume Stroud and Emmy Li and Yang, {Marty G.} and Benyam Kinde and Griffith, {Eric C.} and Boyan Bonev and Greenberg, {Michael E.}",
note = "Funding Information: We would like to thank the Rett Syndrome Research Trust for support of this work, along with NIH F32NS101739 and K99NS112415 (L.D.B.), K08NS101064 (W.R.), and R01NS048276 (M.E.G.). We would like to thank Charles Danko and Ed Rice for PRO-seq protocols; Hojoong Kwak for code for analyzing elongation rates; Matt Lyst for MeCP2 immunoprecipitation protocols; and Adrian Bird and Gail Mandel as well as members of their laboratories, Drs. Karen Adelman, Telmo Henriques, Erin Duffy, David Harmin, Liming Liang, and Harrison Gabel, for helpful discussions. L.D.B. and W.R. designed, performed, and analyzed most experiments in the study. A.W.G. T.W. A.S. H.S. E.L. M.G.Y. and B.K. performed additional experiments. B.B. analyzed Hi-C data. L.D.B, W.R. E.C.G. and M.E.G. wrote the manuscript. M.E.G. advised on all aspects of the study. M.E.G is on the Board of Directors and holds equity in Allergan, plc. Funding Information: We would like to thank the Rett Syndrome Research Trust for support of this work, along with NIH F32NS101739 and K99NS112415 (L.D.B.), K08NS101064 (W.R.), and R01NS048276 (M.E.G.). We would like to thank Charles Danko and Ed Rice for PRO-seq protocols; Hojoong Kwak for code for analyzing elongation rates; Matt Lyst for MeCP2 immunoprecipitation protocols; and Adrian Bird and Gail Mandel as well as members of their laboratories, Drs. Karen Adelman, Telmo Henriques, Erin Duffy, David Harmin, Liming Liang, and Harrison Gabel, for helpful discussions. Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",
year = "2020",
month = jan,
day = "16",
doi = "10.1016/j.molcel.2019.10.032",
language = "English (US)",
volume = "77",
pages = "294--309.e9",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "2",
}