R.F. Luco et al., “Regulation of alternative splicing by histone modifications,” Science, 327:996–1000, 2010. (ID: 2000983)
Alternative splicing, or the shuffling of exons that ultimately become an mRNA message, is one of the “last of the fundamental gene expression mechanisms we don’t understand,” said Tom Misteli from the National Cancer Institute in Bethesda. His group showed that epigenetic changes—methylation and acetylation of histones—govern that process.
Since previous studies had shown that splicing was affected by the speed of DNA transcription, Misteli hypothesized that histone modifications might slow transcription, and therefore affect splicing. His lab, however, found that chromatin affected not the speed, but the selection of splice sites: methylation of lysine 36 on histone H3, for example, promotes the inclusion of exons regulated by the PTB protein.
But how was the message transmitted from the DNA-bound histones to RNA? After talking to collaborator Olivia Pereira-Smith and the University of Texas, Misteli realized that a protein he had observed binding to both the H3 histone and RNA also interacted with PTB. That protein, MRG15, appeared to be the adaptor protein he was looking for. Indeed, over-expressing MRG15 instigated PTB-regulated splicing. “We got a bit little lucky,” admits Misteli.
The results highlight the idea that “epigenetic processes not only control gene expression but also can directly affect the type of protein product” produced, says F1000 member Andrea Mattevi. The next question, says Misteli, is to find what regulates the histone modifications that regulate the splicing.
F1000 evaluators: A. Mattevi (Univ. of Pavia) • L. Ringrose (Inst. of Molecular Biotechnology GmbH) • L. Desgroseillers (Univ. de Montréal) • Y. Chen and G. Varani (Univ. of Washington)
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