title: Neuronal MeCP2 is expressed at near histone-octamer levels and globally alters the chromatin state.
abstract: MeCP2 is a nuclear protein with an affinity for methylated DNA that can recruit histone deacetylases. Deficiency or excess of MeCP2 causes severe neurological problems, suggesting that the number of molecules per cell must be precisely regulated. We quantified MeCP2 in neuronal nuclei and found that it is nearly as abundant as the histone octamer. Despite this high abundance, MeCP2 associates preferentially with methylated regions, and high-throughput sequencing showed that its genome-wide binding tracks methyl-CpG density. MeCP2 deficiency results in global changes in neuronal chromatin structure, including elevated histone acetylation and a doubling of histone H1. Neither change is detectable in glia, where MeCP2 occurs at lower levels. The mutant brain also shows elevated transcription of repetitive elements. Our data argue that MeCP2 may not act as a gene-specific transcriptional repressor in neurons, but might instead dampen transcriptional noise genome-wide in a DNA methylation-dependent manner.
authors.affiliation: Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh EH9 3JR, UK.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Skene
authors.forename: Robert S
authors.initials: RS
authors.lastname: Illingworth
authors.forename: Shaun
authors.initials: S
authors.lastname: Webb
authors.forename: Alastair R W
authors.initials: AR
authors.lastname: Kerr
authors.forename: Keith D
authors.initials: KD
authors.lastname: James
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Turner
authors.forename: Rob
authors.initials: R
authors.lastname: Andrews
authors.forename: Adrian P
authors.initials: AP
authors.lastname: Bird
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism*; D018899:CpG Islands; D019175:DNA Methylation; D016678:Genome; D006657:Histones / Q000378:metabolism*; D051783:Methyl-CpG-Binding Protein 2 / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009707:Nucleosomes / Q000378:metabolism; D011485:Protein Binding; D055503:Protein Multimerization; D014158:Transcription, Genetic
chemical_list: D002843:Chromatin; D006657:Histones; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D009707:Nucleosomes