Review
Design principles of interconnections between chromatin and pre-mRNA splicing

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In human cell nuclei, the vast majority of mRNA precursors (pre-mRNA) are spliced in more than one way. The process of alternative splicing creates enormous biological complexity from a limited number of genes, and its misregulation often leads to disease. Splicing regulation relies primarily on RNA-binding proteins that recognize specific target features in the pre-mRNA. Evidence accumulated over the past decade has further shown that most splicing occurs co-transcriptionally and that transcription modulates splicing. More recently, chromatin emerged as a novel node in the network of splicing regulatory interactions. Chromatin structure influences splicing choices but splicing can also actively modulate the pattern of histone modification in chromatin. This review discusses how splicing, transcription and chromatin are interwoven bi-directionally.

Section snippets

Regulation of gene expression by alternative splicing

Removal of introns from pre-mRNAs through splicing provides a versatile means of genetic regulation. Alternative splicing (AS) allows a single gene to generate multiple transcripts, thus expanding transcriptome and proteome diversity in metazoans [1]. In human cells, nearly all genes produce multiple mRNA products through the use of alternative splice sites 2, 3, and disruption of splicing contributes to many human genetic diseases, either as a direct cause, a modifier of disease severity, or a

Multiple layers of splicing regulation

Excision of introns with single nucleotide precision relies on the spliceosome, an elaborate macromolecular machine composed of uridine-rich small nuclear RNAs (UsnRNAs) packaged as ribonucleoprotein particles (snRNPs) that function in conjunction with over 200 distinct non-snRNP auxiliary proteins [19]. Splicing regulation relies on spliceosomal snRNAs and proteins that, in conjunction with other trans-acting splicing factors, recognize specific target features in the pre-mRNA. Introns are

Chromatin structure and transcriptional activity influence splicing

Two decades ago, Adami and Babiss proposed for the first time that splicing can be modulated by chromatin following the observation that two copies of a viral gene in the same nucleus were spliced differentially [29]. They speculated that cellular pre-mRNA splicing might be regulated by chromatin and a potential mechanism could involve changes in transcriptional elongation rates or transcriptional pausing [29]. This visionary model was confirmed approximately 10 years later by Kornblihtt and

Bidirectional coupling between chromatin structure and transcriptional activity

Transcription of a chromatin template involves multiple protein factors that help RNAP II traverse the nucleosome barrier. A recent study shows that RNAP II pauses frequently throughout the body of genes and each pause occurs just before a nucleosome [41]. In addition to a plethora of transcription activators and chromatin remodeling factors, it appears that RNAP II itself is required to break DNA–histone contacts, at least at the promoter [42]. However, during transcription elongation, RNAP II

Splicing reaches back to transcription and chromatin

Introns have a stimulatory effect on gene expression in both yeast and mice 50, 51, 52, and a growing body of recent evidence indicates that the mechanism involves a direct effect of splicing on initiation, elongation and termination of RNAP II-dependent transcription. The model whereby splicing enhances transcription was first suggested by Fong and Zhou, who found that spliceosomal snRNPs interact with transcription elongation factor TAT-SF1 [53]. TAT-SF1–snRNP complexes can stimulate

Concluding remarks

As cells differentiate and respond to stimuli in the human body, over one million different proteins are likely to be produced from less than 25 000 genes. Among other processes, a single gene creates different types of proteins by AS of the primary transcripts. Despite tremendous advances, we do not yet understand the global rules that govern AS. During the past few years, large amounts of genome-wide data have revealed that exons and introns differ in chromatin structure. This, together with

Acknowledgments

We thank Nick Proudfoot, Alberto Kornblihtt and Gil Ast for stimulating discussions and critical comments. Our laboratory is supported by grants from Fundação para a Ciência e Tecnologia, Portugal (PTDC/SAU-GMG/113440/2009 and PTDC/BIA-BCM/111451/2009) and the European Commission (ITN-2011-289007).

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