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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Journal ArticleDOI
Sequence features accurately predict genome-wide MeCP2 binding in vivo.
H. Tomas Rube,H. Tomas Rube,Wooje Lee,Wooje Lee,Miroslav Hejna,Huaiyang Chen,Dag H. Yasui,John F. Hess,Janine M. LaSalle,Jun S. Song,Qizhi Gong +10 more
TL;DR: Using high-resolution MeCP2-binding data, it is shown that DNA sequence features alone can predict binding with 88% accuracy and that previously reported genome-wide association with methylation is in part due to Me CP2's affinity to GC-rich chromatin.
Journal ArticleDOI
Stress and the Emerging Roles of Chromatin Remodeling in Signal Integration and Stable Transmission of Reversible Phenotypes.
TL;DR: The potential molecular mechanism(s) of gene regulation associated with chromatin modeling and programming of endocrine and behavioral responses to stress are discussed, including alterations in DNA methylation and the role of DNA repair machinery.
Journal ArticleDOI
Loss of MECP2 leads to activation of p53 and neuronal senescence
Masao Ohashi,Elena Korsakova,Denise E. Allen,Peiyee Lee,Kai Fu,Benni Vargas,Jessica K Cinkornpumin,Carlos Salas,Jennifer C Park,Igal Germanguz,Justin Langerman,Contantinos Chronis,Edward Kuoy,Stephen Tran,Xinshu Xiao,Matteo Pellegrini,Kathrin Plath,William E. Lowry +17 more
TL;DR: The induction of P53 appeared to affect dendritic branching in Rett neurons, as P53 inhibition restored dendrite complexity, suggesting that this disease-in-a-dish model can provide relevant insights into the human disorder.
Journal ArticleDOI
Unusual Characteristics of the DNA Binding Domain of Epigenetic Regulatory Protein MeCP2 Determine Its Binding Specificity
Sergei Khrapunov,Christopher D. Warren,Huiyong Cheng,Esther R. Berko,John M. Greally,Michael Brenowitz +5 more
TL;DR: It is shown that solution conditions with physiological or greater salt concentrations or the presence of nonspecific competitor DNA is necessary for the MBD to discriminate mCpG from CpG with high specificity, and it displays an unusually high affinity for single-stranded DNA independent of modification or sequence.
Journal ArticleDOI
Histone and DNA Modifications as Regulators of Neuronal Development and Function.
Stavros Lomvardas,Tom Maniatis +1 more
TL;DR: The interplay between DNA methylation and Polycomb-mediated repression during neuronal differentiation, the role of DNA methylisation and long-range enhancer-promoter interactions in Protocadherin promoter choice, and the contribution of heterochromatic silencing and nuclear organization in singular olfactory receptor expression are described.
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Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2.
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TL;DR: This study reports the first disease-causing mutations in RTT and points to abnormal epigenetic regulation as the mechanism underlying the pathogenesis of RTT.