Specific histone modifications associate with alternative exon selection during mammalian development.

Elizabeth A Heller,Casey S Greene,Qiwen Hu

doi:10.1093/nar/gkaa248

Elizabeth A Heller, Casey S Greene + Show 1 more

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https://doi.org/10.1093/nar/gkaa248

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Abstract

Alternative splicing (AS) is frequent during early mouse embryonic development. Specific histone post-translational modifications (hPTMs) have been shown to regulate exon splicing by either directly recruiting splice machinery or indirectly modulating transcriptional elongation. In this study, we hypothesized that hPTMs regulate expression of alternatively spliced genes for specific processes during differentiation. To address this notion, we applied an innovative machine learning approach to relate global hPTM enrichment to AS regulation during mammalian tissue development. We found that specific hPTMs, H3K36me3 and H3K4me1, play a role in skipped exon selection among all the tissues and developmental time points examined. In addition, we used iterative random forest model and found that interactions of multiple hPTMs most strongly predicted splicing when they included H3K36me3 and H3K4me1. Collectively, our data demonstrated a link between hPTMs and alternative splicing which will drive further experimental studies on the functional relevance of these modifications to alternative splicing.

Highlights

Alternative splicing (AS) is a regulatory mechanism of gene expression that enables one gene to generate multiple mRNA isoforms that may have different functions or properties
Alternative splicing has been shown to contribute to cell differentiation, tissue identity and organ development [2, 29]
To identify AS events associated with tissue development, we analyzed ENCODE RNA-seq data [30] derived from mouse embryonic tissues at multiple developmental time points

Summary

Introduction

Alternative splicing (AS) is a regulatory mechanism of gene expression that enables one gene to generate multiple mRNA isoforms that may have different functions or properties. Seq analyses of the whole transcriptome have revealed the high prevalence of AS in many organisms (human and mouse: 90%, drosophila: 60%) [1, 2]. AS has been shown to contribute to cell differentiation, tissue identity and organ development [2]. The expression of a specific isoform is often necessary to maintain tissue identity and function, while selection between alternative isoforms drives tissue development and cell differentiation [3]. A number of studies aimed at revealing the importance of AS during development find that AS and specific isoform expression is frequent during early mouse embryonic development [4-6]. Many alternatively spliced isoforms show a dramatic change in relative expression levels during embryonic to adult development in C.elegans [7]

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