MeCP2 binds to 5hmc enriched within active genes and accessible chromatin in the nervous system
TLDR
In this paper, a quantitative, genome-wide analysis of 5hmC, 5-methylcytosine (5mC), and gene expression in differentiated CNS cell types in vivo is presented.Abstract:
SUMMARY The high level of 5-hydroxymethylcytosine (5hmC) present in neuronal genomes suggests that mechanisms interpreting 5hmC in the CNS may differ from those present in embryonic stem cells. Here, we present quantitative, genome-wide analysis of 5hmC, 5-methylcytosine (5mC), and gene expression in differentiated CNS cell types in vivo. We report that 5hmC is enriched in active genes and that, surprisingly, strong depletion of 5mC is observed over these regions. The contribution of these epigenetic marks to gene expression depends critically on cell type. We identify methyl-CpG-binding protein 2 (MeCP2) as the major 5hmC-binding protein in the brain and demonstrate that MeCP2 binds 5hmC- and 5mC-containing DNA with similar high affinities. The Rett-syndrome-causing mutation R133C preferentially inhibits 5hmC binding. These findings support a model in which 5hmC and MeCP2 constitute a cell-specific epigenetic mechanism for regulation of chromatin structure and gene expression.read more
Citations
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The molecular basis of variable phenotypic severity among common missense mutations causing Rett syndrome.
Kyla Brown,Jim Selfridge,Sabine Lagger,John C. Connelly,Dina De Sousa,Alastair R.W. Kerr,Shaun Webb,Jacky Guy,Cara Merusi,Martha V. Koerner,Adrian Bird +10 more
TL;DR: An Mecp2 allelic series representing the three most common missense Rett syndrome (RTT) mutations is described, finding that MeCP2[T158M] is significantly less stable than Me CP2[R133C], which may account for the divergent clinical impact of the mutations.
Journal ArticleDOI
Implications of DNA Methylation in Parkinson’s Disease
Ernesto Miranda-Morales,Karin Meier,Ada Agustina Sandoval-Carrillo,José M. Salas-Pacheco,Paola Vázquez-Cárdenas,Oscar Arias-Carrión +5 more
TL;DR: Although the search for significant DNA methylation changes and gene expression analyses of PD-associated genes have yielded inconsistent and contradictory results, epigenetic modifications remain under investigation for their potential to reveal the link between environmental risk factors and the development of PD.
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Snf2h-mediated chromatin organization and histone H1 dynamics govern cerebellar morphogenesis and neural maturation
Matías Alvarez-Saavedra,Matías Alvarez-Saavedra,Yves De Repentigny,Pamela S. Lagali,Edupuganti V.S. Raghu Ram,Keqin Yan,Emile Hashem,Emile Hashem,Danton Ivanochko,Danton Ivanochko,Michael S. Huh,Doo Yang,Alan J. Mears,Matthew A. M. Todd,Matthew A. M. Todd,Chelsea P. Corcoran,Erin A. Bassett,Nicholas Tokarew,Juraj Kokavec,Romit Majumder,Ilya Ioshikhes,Valerie A. Wallace,Valerie A. Wallace,Rashmi Kothary,Rashmi Kothary,Eran Meshorer,Tomas Stopka,Arthur I. Skoultchi,David J. Picketts,David J. Picketts +29 more
TL;DR: It is shown that mice conditionally inactivated for Snf2h in neural progenitors have reduced levels of histone H1 and H2A variants that compromise chromatin fluidity and transcriptional programs within the developing cerebellum.
Journal ArticleDOI
Cell-Type-Specific Translation Profiling Reveals a Novel Strategy for Treating Fragile X Syndrome
Sophie R. Thomson,Sang S. Seo,Stephanie A. Barnes,Susana R. Louros,Melania Muscas,Owen Dando,Caoimhe Kirby,David J. A. Wyllie,Giles E. Hardingham,Peter C. Kind,Emily K. Osterweil +10 more
TL;DR: Surprisingly, enhancement rather than inhibition of M4 activity normalizes core phenotypes in the Fmr1−/y, including excessive protein synthesis, exaggerated mGluR-LTD, and audiogenic seizures.
Journal ArticleDOI
A High-Resolution Imaging Approach to Investigate Chromatin Architecture in Complex Tissues
TL;DR: ChromATin is presented as a powerful in situ method for examining cell-type-specific differences in chromatin architecture in complex tissues and is applied to examine how the genome is organized in the mammalian brain using female Rett syndrome mice.
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