CTCF-promoted RNA polymerase II pausing links DNA methylation to splicing

Shukla, Sanjeev; Kavak, Erşen; Gregory, Melissa K.; Imashimizu, Masahiko; Shutinoski, Bojan; Kashlev, Mikhail; Oberdoerffer, Philipp; Sandberg, Rickard; Oberdoerffer, Shalini

doi:10.1038/nature10442

Cited by 859 publications

(1,022 citation statements)

References 52 publications

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“…Because DNA methylation has been implicated in the regulation of mRNA splicing, an interesting question is whether different exon types in alternative splicing differ in the level of DNA methylation (24). We therefore examine the mCG densities separately for alternatively spliced exons (ASEs) and constitutively spliced exons (CSEs ; Table S1).…”

Section: Resultsmentioning

confidence: 99%

Position-dependent correlations between DNA methylation and the evolutionary rates of mammalian coding exons

Chuang

Chen

2012

Proc. Natl. Acad. Sci. U.S.A.

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DNA cytosine methylation is a central epigenetic marker that is usually mutagenic and may increase the level of sequence divergence. However, methylated genes have been reported to evolve more slowly than unmethylated genes. Hence, there is a controversy on whether DNA methylation is correlated with increased or decreased protein evolutionary rates. We hypothesize that this controversy has resulted from the differential correlations between DNA methylation and the evolutionary rates of coding exons in different genic positions. To test this hypothesis, we compare human-mouse and human-macaque exonic evolutionary rates against experimentally determined single-base resolution DNA methylation data derived from multiple human cell types. We show that DNA methylation is significantly related to within-gene variations in evolutionary rates. First, DNA methylation level is more strongly correlated with C-to-T mutations at CpG dinucleotides in the first coding exons than in the internal and last exons, although it is positively correlated with the synonymous substitution rate in all exon positions. Second, for the first exons, DNA methylation level is negatively correlated with exonic expression level, but positively correlated with both nonsynonymous substitution rate and the sample specificity of DNA methylation level. For the internal and last exons, however, we observe the opposite correlations. Our results imply that DNA methylation level is differentially correlated with the biological (and evolutionary) features of coding exons in different genic positions. The first exons appear more prone to the mutagenic effects, whereas the other exons are more influenced by the regulatory effects of DNA methylation.methylation-associated mutation | exon evolution | genomics | deep sequencing | bioinformatics D NA methylation is a common form of epigenetic modification that is important for a variety of biological functions, including transcriptional silencing (1), genomic imprinting (2), X-chromosome inactivation (3), the silencing of transposons (4), tumorigenesis (5), and the differentiation of pluripotent cells (6). DNA methylation is unevenly distributed in the human genome. For example, the CpG islands near the promoter regions of active genes tend to be unmethylated (7-10), because methylation in these regions is strongly correlated with transcriptional suppression (8). It has also been reported that exons tend to be more methylated than introns, and that sharp transitions of methylation occur at exonintron boundaries in human (6). Moreover, the level of DNA methylation also varies among exonic regions. The levels of DNA methylation in the first exons were reported to be lower than in downstream exons, and tightly linked to transcriptional silencing (11). In addition, the level of DNA methylation exhibits a slight but sharp step-down at the transcriptional terminal sites (6).In terms of molecular evolution, DNA methylation is relevant in two aspects. First, DNA methylation can significantly increase the rate of spontan...

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Section: Resultsmentioning

confidence: 99%

Position-dependent correlations between DNA methylation and the evolutionary rates of mammalian coding exons

Chuang

Chen

2012

Proc. Natl. Acad. Sci. U.S.A.

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“…In Z. nevadensis, the rate of methylation was found to be particularly high relative to other insects 57,58 . DNA methylation is involved with gene regulation 65 and alternative splicing 66 , and may be crucial to phenotypic plasticity such as caste differentiation. There is evidence that methylation plays a role in honey bee caste determination, specifically affecting the proportion of brood likely to develop into queens 67 .…”

Section: Discussionmentioning

confidence: 99%

Molecular traces of alternative social organization in a termite genome

et al. 2014

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Although eusociality evolved independently within several orders of insects, research into the molecular underpinnings of the transition towards social complexity has been confined primarily to Hymenoptera (for example, ants and bees). Here we sequence the genome and stage-specific transcriptomes of the dampwood termite Zootermopsis nevadensis (Blattodea) and compare them with similar data for eusocial Hymenoptera, to better identify commonalities and differences in achieving this significant transition. We show an expansion of genes related to male fertility, with upregulated gene expression in male reproductive individuals reflecting the profound differences in mating biology relative to the Hymenoptera. For several chemoreceptor families, we show divergent numbers of genes, which may correspond to the more claustral lifestyle of these termites. We also show similarities in the number and expression of genes related to caste determination mechanisms. Finally, patterns of DNA methylation and alternative splicing support a hypothesized epigenetic regulation of caste differentiation.

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“…In a study that monitored RNAPII tracking along long tumour necrosis factor-alpha responsive genes, pausing of RNAPII was observed at CTCF-and cohesin-bound sites [61]. This pausing can serve to incorporate weak exons and, therefore, facilitate alternative splicing [62]. Thus, intra-and intergenic CTCF sites can have many different roles.…”

Section: Ctcf and Other Binding Partnersmentioning

confidence: 99%

CTCF: the protein, the binding partners, the binding sites and their chromatin loops

Holwerda

Laat

2013

Phil. Trans. R. Soc. B

198

170

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CTCF has it all. The transcription factor binds to tens of thousands of genomic sites, some tissue-specific, others ultra-conserved. It can act as a transcriptional activator, repressor and insulator, and it can pause transcription. CTCF binds at chromatin domain boundaries, at enhancers and gene promoters, and inside gene bodies. It can attract many other transcription factors to chromatin, including tissue-specific transcriptional activators, repressors, cohesin and RNA polymerase II, and it forms chromatin loops. Yet, or perhaps therefore, CTCF's exact function at a given genomic site is unpredictable. It appears to be determined by the associated transcription factors, by the location of the binding site relative to the transcriptional start site of a gene, and by the site's engagement in chromatin loops with other CTCF-binding sites, enhancers or gene promoters. Here, we will discuss genome-wide features of CTCF binding events, as well as locus-specific functions of this remarkable transcription factor.

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CTCF-promoted RNA polymerase II pausing links DNA methylation to splicing

Cited by 859 publications

References 52 publications

Position-dependent correlations between DNA methylation and the evolutionary rates of mammalian coding exons

Position-dependent correlations between DNA methylation and the evolutionary rates of mammalian coding exons

Molecular traces of alternative social organization in a termite genome

CTCF: the protein, the binding partners, the binding sites and their chromatin loops

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