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Connections between chromatin signatures and splicing

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Abstract Splicing and alternative splicing are involved in the expression of most human genes, playing key roles in differentiation, cell cycle progression, and development. Misregulation of splicing is frequently associated to disease, which imposes a better understanding of the mechanisms underlying splicing regulation. Accumulated evidence suggests that multiple trans‐acting factors and cis‐regulatory elements act together to determine tissue‐specific splicing patterns. Besides, as splicing is often cotranscriptional, a complex picture emerges in which splicing regulation not only depends on the balance of splicing factor binding to their pre‐mRNA target sites but also on transcription‐associated features such as protein recruitment to the transcribing machinery and elongation kinetics. Adding more complexity to the splicing regulation network, recent evidence shows that chromatin structure is another layer of regulation that may act through various mechanisms. These span from regulation of RNA polymerase II elongation, which ultimately determines splicing decisions, to splicing factor recruitment by specific histone marks. Chromatin may not only be involved in alternative splicing regulation but in constitutive exon recognition as well. Moreover, splicing was found to be necessary for the proper ‘writing’ of particular chromatin signatures, giving further mechanistic support to functional interconnections between splicing, transcription and chromatin structure. These links between chromatin configuration and splicing raise the intriguing possibility of the existence of a memory for splicing patterns to be inherited through epigenetic modifications. WIREs RNA 2013, 4:77–91. doi: 10.1002/wrna.1142 This article is categorized under: RNA Processing > Splicing Mechanisms RNA Processing > Splicing Regulation/Alternative Splicing

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Models of alternative splicing regulation through chromatin structure. (a) Intragenic histone acetylation induces chromatin relaxation favoring high RNA polymerase II (RNAPII) elongation rates and ultimately inducing exon skipping. (b) Intragenic H3K9 methylation induces DNA compactation into chromatin by HP1 recruitment. Accordingly, RNAPII elongation rates decrease and alternative exon inclusion is favored.

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Model of splicing‐dependent H3K36me3 deposition.68 As RNA polymerase II (RNAPII) transcribes and productive spliceosomes are assembled, recruitment of HYPB/Setd2 to the CTD is enhanced and intragenic H3K36me3 levels increase.

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Model of alternative splicing regulation by splicing factor recruitment to specific histone marks described by Luco et al.66 for PTB‐dependent exon skipping. The inhibiting splicing factor binding to the pre‐mRNA is favored when it also binds H3K36me3 via an adaptor protein. When H3K36me3 intragenic levels are low and H3K4me3 are high (left panel), binding of the inhibitor factor to the pre‐mRNA is disfavored and exon inclusion occurs. Conversely, when H3K36me3 intragenic levels are high and H3K4me3 are low (right panel), the inhibiting splicing factor is recruited to chromatin so its binding to pre‐mRNA is favored and exon skipping occurs.

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Model of alternative splicing regulation by DNA methylation and CTCF accumulation described for exon 5 (E5) of the CD45 gene by Shukla et al.86 (a) E5 skipping is favored by fast RNA polymerase II (RNAPII) elongation rates promoted by specific DNA methylation in the exonic region that inhibits CTCF binding. E4 and E6 skipping, on the other hand, is promoted by hnRNPL binding to pre‐mRNA. (b) In the absence of DNA methylation, CTCF binds to E5 DNA where it creates roadblocks to RNAPII elongation favoring E5 recognition and inclusion. E4 and E6 skipping is not affected by this mechanism.

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