MeCP2 binds to 5hmc enriched within active genes and accessible chromatin in the nervous system
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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
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Negative Allosteric Modulation of mGluR5 Partially Corrects Pathophysiology in a Mouse Model of Rett Syndrome.
Jifang Tao,Jifang Tao,Hao Wu,Amanda A. Coronado,Amanda A. Coronado,Elizabeth de Laittre,Elizabeth de Laittre,Emily K. Osterweil,Yi Zhang,Yi Zhang,Yi Zhang,Mark F. Bear,Mark F. Bear +12 more
TL;DR: It is shown in a mouse model of Rett syndrome (Mecp2 KO) that metabotropic glutamate receptor 5 (mGluR5)- and protein-synthesis-dependent synaptic plasticity are abnormal in the hippocampus, suggesting a potential mechanistic link between MeCP2-mediated transcription regulation and mGLUR5/FMRP-mediated protein translation regulation through coregulation of a subset of genes relevant to synaptic functions.
Journal ArticleDOI
Misregulation of Alternative Splicing in a Mouse Model of Rett Syndrome.
Ronghui Li,Qiping Dong,Xinni Yuan,Xin Zeng,Yu Gao,Cassandra Chiao,Hongda Li,Xinyu Zhao,Sunduz Keles,Zefeng Wang,Zefeng Wang,Qiang Chang +11 more
TL;DR: This study identified direct physical interaction between MeCP2 and splicing factors, a novel Me CP2 target gene, and established functional connection between a specific RNA splicing change and synaptic phenotypes in RTT mice.
Journal ArticleDOI
Developmental changes and sex differences in DNA methylation and demethylation in hypothalamic regions of the mouse brain
TL;DR: Tet expression and activity are elevated during neonatal brain development, and may play important roles in sexual differentiation of the brain, mirroring developmental changes in gene expression.
Journal ArticleDOI
MeCP2-Related Diseases and Animal Models
TL;DR: This work will discuss how MeCP2 emerges as a key epigenetic player in human neurodevelopmental, neurological, and non-neurological disorders, and review the current knowledge on Me CP2-related diseases, including Rett Syndrome, Angelman Syndrome, Fetal Alcohol Spectrum Disorder, Hirschsprung disease, and Cancer.
Journal ArticleDOI
The 5-Hydroxymethylcytosine (5hmC) Reader UHRF2 Is Required for Normal Levels of 5hmC in Mouse Adult Brain and Spatial Learning and Memory.
Ruoyu Chen,Qiao Zhang,Xiaoya Duan,Philippe York,Guo-Dong Chen,Pengcheng Yin,Haijun Zhu,Meichen Xu,Peilin Chen,Qihan Wu,Dali Li,Jacques Samarut,Guoliang Xu,Pumin Zhang,Xiaohua Cao,Jiwen Li,Jiemin Wong,Jiemin Wong +17 more
TL;DR: In mice, UHRF2 is more abundantly expressed in the brain and a few other tissues, and gene expression profiling uncovers a role for UHRf2 in regulating neuron-related gene expression, and provides evidence that U HRF2 binds 5hmC in cells but does not appear to affect the TET1 enzymatic activity.
References
More filters
Journal ArticleDOI
Differential expression analysis for sequence count data.
Simon Anders,Wolfgang Huber +1 more
TL;DR: A method based on the negative binomial distribution, with variance and mean linked by local regression, is proposed and an implementation, DESeq, as an R/Bioconductor package is presented.
Journal ArticleDOI
Mapping and quantifying mammalian transcriptomes by RNA-Seq.
TL;DR: Although >90% of uniquely mapped reads fell within known exons, the remaining data suggest new and revised gene models, including changed or additional promoters, exons and 3′ untranscribed regions, as well as new candidate microRNA precursors.
Journal ArticleDOI
Bioconductor: open software development for computational biology and bioinformatics
Robert Gentleman,Vincent J. Carey,Douglas M. Bates,Benjamin M. Bolstad,Marcel Dettling,Sandrine Dudoit,Byron Ellis,Laurent Gautier,Yongchao Ge,Jeff Gentry,Kurt Hornik,Torsten Hothorn,Wolfgang Huber,Stefano Maria Iacus,Rafael A. Irizarry,Friedrich Leisch,Cheng Li,Martin Maechler,A. J. Rossini,Günther Sawitzki,Colin A. Smith,Gordon K. Smyth,Luke Tierney,Jean Yang,Jianhua Zhang +24 more
TL;DR: Details of the aims and methods of Bioconductor, the collaborative creation of extensible software for computational biology and bioinformatics, and current challenges are described.
Journal ArticleDOI
Conversion of 5-Methylcytosine to 5-Hydroxymethylcytosine in Mammalian DNA by MLL Partner TET1
Mamta Tahiliani,Kian Peng Koh,Yinghua Shen,William A. Pastor,Hozefa S. Bandukwala,Yevgeny Brudno,Suneet Agarwal,Lakshminarayan M. Iyer,David R. Liu,L. Aravind,Anjana Rao +10 more
TL;DR: It is shown here that TET1, a fusion partner of the MLL gene in acute myeloid leukemia, is a 2-oxoglutarate (2OG)- and Fe(II)-dependent enzyme that catalyzes conversion of 5mC to 5-hydroxymethylcytosine (hmC) in cultured cells and in vitro.
Journal ArticleDOI
Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2.
Ruthie E. Amir,Ignatia B. Van den Veyver,Mimi Wan,Charles Q. Tran,Uta Francke,Huda Y. Zoghbi +5 more
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.