Regulation of Alternative Splicing by Histone Modifications

By R. Luco, Qun Pan, Kaoru Tominaga, Benjamin J. Blencowe, O. Pereira-smith, Tom Misteli. Science, 2010

1,112 citations recorded by the source corpus.

Histones and Alternative Splicing Alternative splicing—the inclusion of different combinations of gene exons within a messenger RNA transcript—occurs in the majority of human genes and is regulated by basal and tissue-specific splicing factors, by transcription kinetics, and by chromatin structure. Luco et al. (p. 996, published online 4 February) analyzed the alternative splicing of the human fibroblast growth factor receptor 2 gene in tissue culture cells and found that inclusion of exon IIIb or IIIc was modulated by the levels of histone H3 lysine 36 trimethylation (H3-K36me3) and H3-K4me3. Histone H3-K36me3 enrichment correlated with binding of the chromatin protein, MRG15. The MRG15 protein in turn recruited the polypyrimidine tract–binding protein (PTB) splicing factor, which acts to repress alternative exon inclusion, thus establishing a direct link between histone modifications and the splicing machinery. Histone modifications regulate alternative splicing through physical cross talk with the splicing machinery. Alternative splicing of pre-mRNA is a prominent mechanism to generate protein diversity, yet its regulation is poorly understood. We demonstrated a direct role for histone modifications in alternative splicing. We found distinctive histone modification signatures that correlate with the splicing outcome in a set of human genes, and modulation of histone modifications causes splice site switching. Histone marks affect splicing outcome by influencing the recruitment of splicing regulators via a chromatin-binding protein. These results outline an adaptor system for the reading of histone marks by the pre-mRNA splicing machinery.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/2c18467af6f3c822a137f612507f556210f05cec

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Citations in the corpus

ngs.plot: Quick mining and visualization of next-generation sequencing data by integrating genomic databases (2014, background): “Exons and their neighbouring regions are known to contain chromatin modifications that may facilitate exon recognition and influence alternative splicing [30-32].”
Learning the sequence determinants of alternative splicing from millions of random sequences. (2015, background): “A potential limitation of our approach is that mRNAs are transcribed from plasmids rather than directly from the genome, especially considering evidence suggesting that chromatin can influence alternative splicing (Luco et al., 2010).”
Complexity of the Alternative Splicing Landscape in Plants[C][W][OPEN] (2013, background): “Although the means by which chromatin modifications affect splicing remain to be elucidated, there are indications that these modifications may directly or indirectly recruit spliceosomal proteins (Luco et al., 2010; Pradeepa et al., 2012; Schor et al., 2012; Tolstorukov et al., 2012; Braunschweig e”
Epigenetics in alternative pre-mRNA splicing (2011, positive): “In line with this interpretation, increasing H3K36me3 levels in the absence of the MRG15 adaptor protein has no effect on FGFR2 alternative splicing (Luco et al., 2010).”
Deep sequencing of subcellular RNA fractions shows splicing to be predominantly co-transcriptional in the human genome but inefficient for lncRNAs (2012, background): “This is consistent with reports that some lncRNAs remain predominantly unspliced, for example, AIRN and KCNQ1OT1 (Sleutels et al. 2002; Mancini- Dinardo et al. 2006).”
MATS: a Bayesian framework for flexible detection of differential alternative splicing from RNA-Seq data (2012, background): “This is the typical experimental setup in most published RNA-Seq studies of alternative splicing including studies of splicing regulators (16,20,42), largely due to the high cost of RNA-Seq to achieve sufficient depth for splicing analysis.”