Intragenic DNA methylation modulates alternative splicing by recruiting MeCP2 to promote exon recognition.
TLDR
The data indicate that intragenic DNA methylation operates in exon definition to modulate alternative RNA splicing and can enhance exon recognition via recruitment of the multifunctional protein MeCP2, which thereby maintains local histone hypoacetylation through the subsequent recruitment of HDACs.Abstract:
Although the function of DNA methylation in gene promoter regions is well established in transcriptional repression, the function of the evolutionarily conserved widespread distribution of DNA methylation in gene body regions remains incompletely understood. Here, we show that DNA methylation is enriched in included alternatively spliced exons (ASEs), and that inhibition of DNA methylation results in aberrant splicing of ASEs. The methyl-CpG-binding protein MeCP2 is enriched in included ASEs, particularly those that are also highly methylated, and inhibition of DNA methylation disrupts specific targeting of MeCP2 to exons. Interestingly, ablation of MeCP2 results in increased histone acetylation and aberrant ASE-skipping events. We further show that inhibition of histone deacetylase (HDAC) activity leads to exon skipping that shows a highly significant degree of overlap with that caused by MeCP2 knockdown. Together, our data indicate that intragenic DNA methylation operates in exon definition to modulate alternative RNA splicing and can enhance exon recognition via recruitment of the multifunctional protein MeCP2, which thereby maintains local histone hypoacetylation through the subsequent recruitment of HDACs.read more
Citations
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Function and information content of DNA methylation
TL;DR: These observations indicate that the underlying DNA sequence largely accounts for local patterns of methylation, which is highly informative when studying gene regulation in normal and diseased cells, and it can potentially function as a biomarker.
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The diverse roles of DNA methylation in mammalian development and disease
TL;DR: The mechanisms and functions of DNA methylation and demethylation in both mice and humans at CpG-rich promoters, gene bodies and transposable elements are discussed and the dynamic erasure and re-establishment in embryonic, germline and somatic cell development is highlighted.
Dissection ofthemethyl-CpG binding domainfromthe chromosomal protein MeCP2
TL;DR: In vitro footprinting indicates that MBD binding can protect a 12 nucleotide region surrounding a methyl-CpG pair, with an approximate dissociation constant of 10(-9) M.
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Intragenic DNA methylation prevents spurious transcription initiation
Francesco Neri,Stefania Rapelli,Anna Krepelova,Danny Incarnato,Caterina Parlato,Giulia Basile,Mara Maldotti,Francesca Anselmi,Salvatore Oliviero +8 more
TL;DR: It is shown that, in mouse embryonic stem cells, Dnmt3b-dependent intragenic DNA methylation protects the gene body from spurious RNA polymerase II entry and cryptic transcription initiation, with implications for intragenics hypomethylation in cancer.
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Genome-wide dynamics of Pol II elongation and its interplay with promoter proximal pausing, chromatin, and exons
TL;DR: Notably, Pol II accelerates dramatically while transcribing through genes, but slows at exons, and intergenic variance in elongation rates is substantial, and is influenced by a positive effect of H3K79me2 and negative effects of exon density and CG content within genes.
References
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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
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Human DNA methylomes at base resolution show widespread epigenomic differences
Ryan Lister,Mattia Pelizzola,Robert H. Dowen,R. David Hawkins,Gary C. Hon,Julian Tonti-Filippini,Joseph R. Nery,Leonard Lee,Zhen Ye,Que Minh Ngo,Lee Edsall,Jessica Antosiewicz-Bourget,Jessica Antosiewicz-Bourget,Ron Stewart,Ron Stewart,Victor Ruotti,Victor Ruotti,A. Harvey Millar,James A. Thomson,Bing Ren,Bing Ren,Joseph R. Ecker +21 more
TL;DR: The first genome-wide, single-base-resolution maps of methylated cytosines in a mammalian genome, from both human embryonic stem cells and fetal fibroblasts, along with comparative analysis of messenger RNA and small RNA components of the transcriptome, several histone modifications, and sites of DNA-protein interaction for several key regulatory factors were presented in this article.
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