Transcriptional elongation and alternative splicing

Dujardin, Geneviève; Lafaille, Celina; Petrillo, Ezequiel; Buggiano, Valeria; Acuña, Luciana Inés Gómez; Fiszbein, Ana; Herz, Micaela Amalia Godoy; Moreno, Nicolás Nieto; Muñoz, Manuel J.; Alló, Mariano; Schor, Ignacio E.; Kornblihtt, Alberto R.

doi:10.1016/j.bbagrm.2012.08.005

Cited by 86 publications

(70 citation statements)

References 72 publications

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“…The effects on splicing fidelity of changing transcription rate could reflect less efficient elimination of splicing errors as a result of perturbing cotranscriptional quality control mechanisms, such as kinetic proofreading of splicing (Hopfield 1974;Semlow and Staley 2012). Additionally, altering transcription elongation rate was reported to change multiple properties of nascent RNA and the chromatin environment around sites of active transcription, affecting alternative splicing decisions (Buratti and Baralle 2004;Dujardin et al 2013;Saldi et al 2016). The CTD was recently shown to form multivalent interactions with low-complexity domains in other proteins, including certain splicing factors, suggesting another mechanism by which RNAPII might affect cotranscriptional splicing, by compartmentalizing these two processes (Harlen and Churchman 2017).…”

Section: Discussionmentioning

confidence: 99%

Transcription rate strongly affects splicing fidelity and cotranscriptionality in budding yeast

et al. 2017

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The functional consequences of alternative splicing on altering the transcription rate have been the subject of intensive study in mammalian cells but less is known about effects of splicing on changing the transcription rate in yeast. We present several lines of evidence showing that slow RNA polymerase II elongation increases both cotranscriptional splicing and splicing efficiency and that faster elongation reduces cotranscriptional splicing and splicing efficiency in budding yeast, suggesting that splicing is more efficient when cotranscriptional. Moreover, we demonstrate that altering the RNA polymerase II elongation rate in either direction compromises splicing fidelity, and we reveal that splicing fidelity depends largely on intron length together with secondary structure and splice site score. These effects are notably stronger for the highly expressed ribosomal protein coding transcripts. We propose that transcription by RNA polymerase II is tuned to optimize the efficiency and accuracy of ribosomal protein gene expression, while allowing flexibility in splice site choice with the nonribosomal protein transcripts.[Supplemental material is available for this article.]Splicing is the process of removing introns from precursor messenger RNAs (pre-mRNAs) and joining adjacent exons to produce spliced mRNA. The excised intron, in the form of a branched lariat, is rapidly debranched and discarded. If genes contain multiple introns, alternative splicing pathways can give rise to distinct mRNA and protein isoforms by using alternative splice sites or by including or excluding particular exons. In human cells, ∼95% of transcripts are alternatively spliced, thereby greatly expanding the coding capacity of the genome (Kornblihtt et al. 2013). Moreover, alternative splicing events that introduce translational stop codons in mRNAs are generally coupled with nonsensemediated decay (NMD) to down-regulate that spliced isoform, offering an additional layer of gene expression regulation (Lewis et al. 2003;Sayani et al. 2008;Kawashima et al. 2014). In Saccharomyces cerevisiae (budding yeast) only ∼5% of genes contain an intron, although they produce ∼27% of total mRNA, because many intron-containing genes are highly expressed (Ares et al. 1999). There is extensive evidence that in both metazoans and budding yeast, the process of splicing occurs as soon as the intron is transcribed and before transcription termination, that is, cotranscriptionally (Alexander et al. 2010b;Ameur et al. 2011;Carrillo Oesterreich et al. 2016). As a result of splicing being cotranscriptional, RNA polymerase II (RNAPII) elongation rate can influence splicing. According to one model, referred to as the "kinetic coupling" model, variations in RNAPII elongation rate can alter the time available, or the "window of opportunity" for upstream splice sites to be recognized before competing downstream splice sites are produced (Roberts et al. 1998;de la Mata et al. 2003;Kornblihtt 2007;Naftelberg et al. 2015;Saldi et al. 2016). Consistent with this model, ...

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Section: Discussionmentioning

confidence: 99%

Transcription rate strongly affects splicing fidelity and cotranscriptionality in budding yeast

et al. 2017

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“…Evidence is accumulating that chromatin modifications, transcription, and splicing are highly integrated, each influencing the other (Braunschweig et al, 2013;Dujardin et al, 2013;Gómez Acuña et al, 2013). Multiple aspects associated with transcription, such as promoter strength, transcription factor occupancy, rate of transcription, speed of RNA polymerase, and chromatin modifications, are known to change AS (Braunschweig et al, 2013).…”

Section: As Regulation By Epigenetic Marks On Dna and Histonesmentioning

confidence: 99%

Complexity of the Alternative Splicing Landscape in Plants

et al. 2013

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Alternative splicing (AS) of precursor mRNAs (pre-mRNAs) from multiexon genes allows organisms to increase their coding potential and regulate gene expression through multiple mechanisms. Recent transcriptome-wide analysis of AS using RNA sequencing has revealed that AS is highly pervasive in plants. Pre-mRNAs from over 60% of intron-containing genes undergo AS to produce a vast repertoire of mRNA isoforms. The functions of most splice variants are unknown. However, emerging evidence indicates that splice variants increase the functional diversity of proteins. Furthermore, AS is coupled to transcript stability and translation through nonsense-mediated decay and microRNA-mediated gene regulation. Widespread changes in AS in response to developmental cues and stresses suggest a role for regulated splicing in plant development and stress responses. Here, we review recent progress in uncovering the extent and complexity of the AS landscape in plants, its regulation, and the roles of AS in gene regulation. The prevalence of AS in plants has raised many new questions that require additional studies. New tools based on recent technological advances are allowing genome-wide analysis of RNA elements in transcripts and of chromatin modifications that regulate AS. Application of these tools in plants will provide significant new insights into AS regulation and crosstalk between AS and other layers of gene regulation.

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“…The mechanism of the recruitment model may mainly depend on specific features of CTD (as mentioned above), whereas the kinetic model is based on the different elongation rates of Pol II, which in turn determine the timing of the presentation of splices sites (47,48).…”

Section: Coupling Of Alternative Splicing To Transcriptionmentioning

confidence: 99%

Mechanism of alternative splicing and its regulation

et al. 2014

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Abstract. Alternative splicing of precursor mRNA is an essential mechanism to increase the complexity of gene expression, and it plays an important role in cellular differentiation and organism development. Regulation of alternative splicing is a complicated process in which numerous interacting components are at work, including cis-acting elements and trans-acting factors, and is further guided by the functional coupling between transcription and splicing. Additional molecular features, such as chromatin structure, RNA structure and alternative transcription initiation or alternative transcription termination, collaborate with these basic components to generate the protein diversity due to alternative splicing.

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Transcriptional elongation and alternative splicing

Cited by 86 publications

References 72 publications

Transcription rate strongly affects splicing fidelity and cotranscriptionality in budding yeast

Transcription rate strongly affects splicing fidelity and cotranscriptionality in budding yeast

Complexity of the Alternative Splicing Landscape in Plants

Mechanism of alternative splicing and its regulation

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