Relationship between nucleosome positioning and progesterone-induced alternative splicing in breast cancer cells

Iannone, Camilla; Pohl, Andy; Papasaikas, Panagiotis; Soronellas, Daniel; Vicent, Guillermo P.; Beato, Miguel; Valcárcel, Juan

doi:10.1261/rna.048843.114

Cited by 37 publications

(29 citation statements)

References 65 publications

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“…Two recent studies assessed the relationship between nucleosome occupancy and alternative splicing. One study found that near alternative exons that are preferentially included in progesterone treated breast cancer cells, the chromatin structure switched from poorly positioned to well-positioned nucleosomes and this rearrangement correlated with increased pol II occupancy consistent with pausing 96 . A second study addressed whether changes in nucleosome occupancy can cause changes in splice site selection by restricting the histone supply in colon carcinoma cells through inhibition of histone mRNA 3’ end formation.…”

Section: Kinetic Coupling: How Elongation Rate Affects Nascent Pre-mrmentioning

confidence: 99%

Coupling of RNA Polymerase II Transcription Elongation with Pre-mRNA Splicing

Saldi

Cortázar

Sheridan

et al. 2016

Journal of Molecular Biology

246

226

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Pre-mRNA maturation frequently occurs at the same time and place as transcription by RNA polymerase II (pol II). The co-transcriptionality of mRNA processing has permitted the evolution of mechanisms that functionally couple transcription elongation with diverse events that occur on the nascent RNA. This review summarizes current understanding of the relationship between transcriptional elongation through a chromatin template and co-transcriptional splicing including alternative splicing decisions that affect the expression of most human genes.

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Section: Kinetic Coupling: How Elongation Rate Affects Nascent Pre-mrmentioning

confidence: 99%

Coupling of RNA Polymerase II Transcription Elongation with Pre-mRNA Splicing

Saldi

Cortázar

Sheridan

et al. 2016

Journal of Molecular Biology

246

226

View full text Add to dashboard Cite

show abstract

“…It has been proposed that this exon-dependent RNAPII accumulation might be influenced by chromatin, because increased nucleosome occupancy has been found at exons as compared with surrounding introns (19,20). Recently, progesterone-dependent nucleosomal changes have been shown to correlate with changes in alternative splicing (21). In addition, some histone posttranslational modifications associated with elongation are enriched in exons.…”

mentioning

confidence: 99%

Defective histone supply causes changes in RNA polymerase II elongation rate and cotranscriptional pre-mRNA splicing

Jimeno-González

Payán-Bravo

Muñoz-Cabello

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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RNA polymerase II (RNAPII) transcription elongation is a highly regulated process that greatly influences mRNA levels as well as pre-mRNA splicing. Despite many studies in vitro, how chromatin modulates RNAPII elongation in vivo is still unclear. Here, we show that a decrease in the level of available canonical histones leads to more accessible chromatin with decreased levels of canonical histones and variants H2A.X and H2A.Z and increased levels of H3.3. With this altered chromatin structure, the RNAPII elongation rate increases, and the kinetics of pre-mRNA splicing is delayed with respect to RNAPII elongation. Consistent with the kinetic model of cotranscriptional splicing, the rapid RNAPII elongation induced by histone depletion promotes the skipping of variable exons in the CD44 gene. Indeed, a slowly elongating mutant of RNAPII was able to rescue this defect, indicating that the defective splicing induced by histone depletion is a direct consequence of the increased elongation rate. In addition, genome-wide analysis evidenced that histone reduction promotes widespread alterations in pre-mRNA processing, including intron retention and changes in alternative splicing. Our data demonstrate that premRNA splicing may be regulated by chromatin structure through the modulation of the RNAPII elongation rate. T he transcription process comprises several steps, including preinitiation complex formation, promoter escape, elongation, and termination (1). Recent reports indicate that elongation rates of RNA polymerase II (RNAPII) in mammals range from 0.5 to 4 kb/min, but which factors are responsible for these differences is still unclear (2-4). One obvious candidate for affecting transcription elongation is chromatin structure. The building block of chromatin is the nucleosome comprising 147 bp of DNA around a histone octamer formed by two H2A-H2B dimers and one H3-H4 tetramer. In vitro experiments have demonstrated that nucleosomes are a barrier for RNAPII transcription elongation (5, 6). We have reported that a nucleosome positioned in the body of a transcription unit impairs RNAPII progression in vivo (7). Furthermore, Weber et al. (8) have shown recently that RNAPII stalls in vivo at the entry site of essentially every transcribed nucleosome in Drosophila. Despite this evidence, it is still unclear whether changes in chromatin structure in different regions of a gene or between different genes can regulate the rate of transcription elongation.Transcription and splicing are coupled processes (9, 10). Splicing occurs cotranscriptionally, and multiple lines of evidence indicate that transcription elongation and splicing influence each other. On one hand, it has been suggested that splicing factors are recruited to the template by the transcription machinery (11, 12). On the other hand, the rate of RNAPII elongation influences splicing. The kinetic model proposes that a slow elongation rate facilitates weak splice-site recognition, promoting the inclusion of alternative exons (13, 14). However, recent studies have ex...

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“…As a matter of fact, SRSF2 is known to play an active role in transcriptional elongation by facilitating RNA polymerase II pause release (Lin et al 2008;Ji et al 2013) and SRSF2-mediated enhanced elongation rates could indeed promote exon skipping by facilitating kinetic competition between alternative sites (Dujardin et al 2013). Nucleosome positioning was also proposed to influence RNA polymerase II elongation rates and AS (Schwartz and Ast 2010;Gómez et al 2013;Iannone and Valcárcel 2013;Iannone et al 2015) and it is interesting, in this regard, that several members of the family of chromatin-associated High-Mobility Group (HMG) proteins were identified in our proteomic analysis. HMGA1 was enriched in C-rs3736234 RNA and knock down of HMGA1 increased OLR1 exon 5 inclusion specifically in the C-rs3736234 minigene.…”

Section: Discussionmentioning

confidence: 93%

Role of six single nucleotide polymorphisms, risk factors in coronary disease, in OLR1 alternative splicing

Tejedor

Tilgner

Iannone

et al. 2015

RNA

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The OLR1 gene encodes the oxidized low-density lipoprotein receptor (LOX-1), which is responsible for the cellular uptake of oxidized LDL (Ox-LDL), foam cell formation in atheroma plaques and atherosclerotic plaque rupture. Alternative splicing (AS) of OLR1 exon 5 generates two protein isoforms with antagonistic functions in Ox-LDL uptake. Previous work identified six single nucleotide polymorphisms (SNPs) in linkage disequilibrium that influence the inclusion levels of OLR1 exon 5 and correlate with the risk of cardiovascular disease. Here we use minigenes to recapitulate the effects of two allelic series (Lowand High-Risk) on OLR1 AS and identify one SNP in intron 4 (rs3736234) as the main contributor to the differences in exon 5 inclusion, while the other SNPs in the allelic series attenuate the drastic effects of this key SNP. Bioinformatic, proteomic, mutational and functional high-throughput analyses allowed us to define regulatory sequence motifs and identify SR protein family members (SRSF1, SRSF2) and HMGA1 as factors involved in the regulation of OLR1 AS. Our results suggest that antagonism between SRSF1 and SRSF2/HMGA1, and differential recognition of their regulatory motifs depending on the identity of the rs3736234 polymorphism, influence OLR1 exon 5 inclusion and the efficiency of Ox-LDL uptake, with potential implications for atherosclerosis and coronary disease.

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Relationship between nucleosome positioning and progesterone-induced alternative splicing in breast cancer cells

Cited by 37 publications

References 65 publications

Coupling of RNA Polymerase II Transcription Elongation with Pre-mRNA Splicing

Coupling of RNA Polymerase II Transcription Elongation with Pre-mRNA Splicing

Defective histone supply causes changes in RNA polymerase II elongation rate and cotranscriptional pre-mRNA splicing

Role of six single nucleotide polymorphisms, risk factors in coronary disease, in OLR1 alternative splicing

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