scholarly journals Evidence for the role of transcription factors in the co-transcriptional regulation of intron retention

2021 ◽  
Author(s):  
Fahad Ullah ◽  
Maayan Salton ◽  
Anireddy S.N. Reddy ◽  
Asa Ben-Hur
Keyword(s):  
Transcription Factors ◽  
Alternative Splicing ◽  
Zinc Finger ◽  
Intron Retention ◽  
Single Gene ◽  
Open Chromatin ◽  
Multiple Transcripts ◽  
High Prevalence ◽  
Retained Introns

Alternative splicing is a widespread regulatory phenomenon that enables a single gene to produce multiple transcripts. Among the different types of alternative splicing, intron retention is one of the least explored despite its high prevalence in both plants and animals. The recent discovery that the majority of splicing is co-transcriptional has led to the finding that chromatin state affects alternative splicing. Therefore it is plausible that transcription factors can regulate splicing outcomes. We provide evidence for this hypothesis by studying regions of open chromatin in retained and excised introns. Using deep learning models designed to distinguish between regions of open chromatin in retained introns and non-retained introns, we identified motifs enriched in IR events with significant hits to known human transcription factors. Our model predicts that the majority of transcription factors that affect intron retention come from the zinc finger family. We demonstrate the validity of these predictions using ChIP-seq data for multiple zinc finger transcription factors and find strong over-representation for their peaks in intron retention events. Availability: Source code available at https://github.com/fahadahaf/chromir

scholarly journals Alternative splicing landscapes in Arabidopsis thaliana across tissues and stress conditions highlight major functional differences with animals

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Guiomar Martín ◽  
Yamile Márquez ◽  
Federica Mantica ◽  
Paula Duque ◽  
Manuel Irimia
Keyword(s):  
Gene Expression ◽  
Arabidopsis Thaliana ◽  
Alternative Splicing ◽  
Stress Responses ◽  
Target Genes ◽  
Intron Retention ◽  
Single Gene ◽  
Exon Skipping ◽  
Environmental Response ◽  
Biotic Stresses

Abstract Background Alternative splicing (AS) is a widespread regulatory mechanism in multicellular organisms. Numerous transcriptomic and single-gene studies in plants have investigated AS in response to specific conditions, especially environmental stress, unveiling substantial amounts of intron retention that modulate gene expression. However, a comprehensive study contrasting stress-response and tissue-specific AS patterns and directly comparing them with those of animal models is still missing. Results We generate a massive resource for Arabidopsis thaliana, PastDB, comprising AS and gene expression quantifications across tissues, development and environmental conditions, including abiotic and biotic stresses. Harmonized analysis of these datasets reveals that A. thaliana shows high levels of AS, similar to fruitflies, and that, compared to animals, disproportionately uses AS for stress responses. We identify core sets of genes regulated specifically by either AS or transcription upon stresses or among tissues, a regulatory specialization that is tightly mirrored by the genomic features of these genes. Unexpectedly, non-intron retention events, including exon skipping, are overrepresented across regulated AS sets in A. thaliana, being also largely involved in modulating gene expression through NMD and uORF inclusion. Conclusions Non-intron retention events have likely been functionally underrated in plants. AS constitutes a distinct regulatory layer controlling gene expression upon internal and external stimuli whose target genes and master regulators are hardwired at the genomic level to specifically undergo post-transcriptional regulation. Given the higher relevance of AS in the response to different stresses when compared to animals, this molecular hardwiring is likely required for a proper environmental response in A. thaliana.

scholarly journals Plant buffering against the high-light stress-induced accumulation of CsGA2ox8 transcripts via alternative splicing to finely tune gibberellin levels and maintain hypocotyl elongation

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Bin Liu ◽  
Shuo Zhao ◽  
Pengli Li ◽  
Yilu Yin ◽  
Qingliang Niu ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Light Intensity ◽  
Intron Retention ◽  
Light Stress ◽  
Photosynthetic Photon Flux Density ◽  
Photon Flux ◽  
Photon Flux Density ◽  
Rna Seq ◽  
Multiple Transcripts ◽  
Novel Transcript

AbstractIn plants, alternative splicing (AS) is markedly induced in response to environmental stresses, but it is unclear why plants generate multiple transcripts under stress conditions. In this study, RNA-seq was performed to identify AS events in cucumber seedlings grown under different light intensities. We identified a novel transcript of the gibberellin (GA)-deactivating enzyme Gibberellin 2-beta-dioxygenase 8 (CsGA2ox8). Compared with canonical CsGA2ox8.1, the CsGA2ox8.2 isoform presented intron retention between the second and third exons. Functional analysis proved that the transcript of CsGA2ox8.1 but not CsGA2ox8.2 played a role in the deactivation of bioactive GAs. Moreover, expression analysis demonstrated that both transcripts were upregulated by increased light intensity, but the expression level of CsGA2ox8.1 increased slowly when the light intensity was >400 µmol·m−2·s−1 PPFD (photosynthetic photon flux density), while the CsGA2ox8.2 transcript levels increased rapidly when the light intensity was >200 µmol·m−2·s−1 PPFD. Our findings provide evidence that plants might finely tune their GA levels by buffering against the normal transcripts of CsGA2ox8 through AS.

scholarly journals Alternative Splicing of Transcription Factors' Genes: Beyond the Increase of Proteome Diversity

2009 ◽  
Vol 2009 ◽  
pp. 1-6 ◽  
Author(s):  
David Talavera ◽  
Modesto Orozco ◽  
Xavier de la Cruz
Keyword(s):  
Transcription Factors ◽  
Alternative Splicing ◽  
Expression Patterns ◽  
Developmental Changes ◽  
Functional Families ◽  
Transcription Regulators ◽  
Alternatively Spliced ◽  
The Impact ◽  
Human And Mouse

Functional modification of transcription regulators may lead to developmental changes and phenotypical differences between species. In this work, we study the influence of alternative splicing on transcription factors in human and mouse. Our results show that the impact of alternative splicing on transcription factors is similar in both species, meaning that the ways to increase variability should also be similar. However, when looking at the expression patterns of transcription factors, we observe that they tend to diverge regardless of the role of alternative splicing. Finally, we hypothesise that transcription regulation of alternatively spliced transcription factors could play an important role in the phenotypical differences between species, without discarding other phenomena or functional families.

scholarly journals Alternative splicing landscapes in Arabidopsis thaliana across tissues and stress conditions highlight major functional differences with animals

2020 ◽  
Author(s):  
Guiomar Martín ◽  
Yamile Márquez ◽  
Federica Mantica ◽  
Paula Duque ◽  
Manuel Irimia
Keyword(s):  
Gene Expression ◽  
Alternative Splicing ◽  
Stress Responses ◽  
Target Genes ◽  
Intron Retention ◽  
Single Gene ◽  
Exon Skipping ◽  
Environmental Response ◽  
Biotic Stresses ◽  
External Stimuli

AbstractBackgroundAlternative splicing (AS) is a widespread regulatory mechanism in multicellular organisms. Numerous transcriptomic and single-gene studies in plants have investigated AS in response to specific conditions, especially environmental stress, unveiling substantial amounts of intron retention that modulate gene expression. However, a comprehensive study contrasting stress-response and tissue-specific AS patterns and directly comparing them with those of animal models is still missing.ResultsWe generated a massive resource for A. thaliana (PastDB; pastdb.crg.eu), comprising AS and gene expression quantifications across tissues, development and environmental conditions, including abiotic and biotic stresses. Harmonized analysis of these datasets revealed that A. thaliana shows high levels of AS (similar to fruitflies) and that, compared to animals, disproportionately uses AS for stress responses. We identified core sets of genes regulated specifically by either AS or transcription upon stresses or among tissues, a regulatory specialization that was tightly mirrored by the genomic features of these genes. Unexpectedly, non-intron retention events, including exon skipping, were overrepresented across regulated AS sets in A. thaliana, being also largely involved in modulating gene expression through NMD and uORF inclusion.ConclusionsNon-intron retention events have likely been functionally underrated in plants. AS constitutes a distinct regulatory layer controlling gene expression upon internal and external stimuli whose target genes and master regulators are hardwired at the genomic level to specifically undergo post-transcriptional regulation. Given the higher relevance of AS in the response to different stresses when compared to animals, this molecular hardwiring is likely required for a proper environmental response in A. thaliana.

scholarly journals Perturbations in HNRNPH1 Splicing and Abundance Affect Global Splicing and Proliferation in Mantle Cell Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 23-24
Author(s):  
Krysta M Coyle ◽  
Quratulain Qureshi ◽  
Prasath Pararajalingam ◽  
Nicole Thomas ◽  
Timothy E Audas ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Intron Retention ◽  
Gene List ◽  
Protein Abundance ◽  
Mantle Cell ◽  
Sirna Knockdown ◽  
Retained Introns

Objectives Mantle cell lymphoma (MCL) is an uncommon B-cell non-Hodgkin lymphoma that is incurable with standard therapies. The genetic drivers of this cancer have not been firmly established and the features known to contribute to differences in clinical course remain limited. We previously discovered non-coding and silent mutations in HNRNPH1 that affect its splicing and contribute to poor outcomes for patients with MCL. We sought to extend our understanding of the mechanisms by which HNRNPH1 contributes to MCL pathology using a combination of in vitro models and integrative analysis of RNA sequencing from MCL tumors. Methods We previously sequenced ribosomal RNA-depleted RNA from 130 MCL tumors. Based on our earlier identification of mutations in HNRNPH1 and altered splicing of this gene, we performed differential splicing analyses using rMATS and leafcutter. We investigated the functional and phenotypic effect of deregulated hnRNP H1 protein through siRNA knockdown. Results Our previous work identified that splicing of HNRNPH1, and not total mRNA expression, correlated with protein abundance in MCL tumors. As a result, our analysis of alternative splicing focused on events associated with altered splicing of HNRNPH1. We identified 155 unique alternative splicing events (ΔPSI > 0.1, FDR < 0.1). Gene ontology analysis identified various aspects of RNA processing which are significantly enriched within this gene list, including mRNA splicing, transport, and metabolic process. This nominates HNRNPH1 as part of the complex network controlling alternative splicing within MCL. Available CLIP-seq in HeLa cells provides evidence for direct interactions between hnRNP H1 and transcripts identified by our analysis (e.g. RBM25, EIF4A1, HNRNPA2B1). Of the 155 events we identified, more than half involved retained introns. Generally, retained introns result in non-productive RNA species, which indicates that this program of intron retention in MCL is a mechanism by which protein abundance can be regulated by hnRNP H1. For all cases with available Mantle Cell Lymphoma International Prognostic Indicator (MIPI) classification, we determined the splicing ratio for HNRNPH1 and observed a general association between high MIPI scores and a lower ratio of non-productive HNRNPH1 transcripts. This suggested that the increased hnRNP H1 abundance we observed in HNRNPH1-mutant tumors contributes to increased proliferation of MCL cells. We verified this in vitro with siRNA knockdown of HNRNPH1 in HEK cells, which resulted in a significant decrease in cell proliferation. Conclusions We have described a pattern of alternative splicing in MCL that is associated with alterations in HNRNPH1 splicing and related protein abundance. The prevalence of retained introns suggests that hnRNP H1 regulates the abundance of protein-coding transcripts via alternative splicing coupled to nonsense-mediated decay. We continue to explore targets of hnRNP H1, a novel oncoprotein in MCL. Disclosures Morin: Celgene: Consultancy.

scholarly journals Alternative Splicing: A Potential Source of Functional Innovation in the Eukaryotic Genome

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Lu Chen ◽  
Jaime M. Tovar-Corona ◽  
Araxi O. Urrutia
Keyword(s):  
Alternative Splicing ◽  
Potential Role ◽  
Single Gene ◽  
Potential Source ◽  
Number Of Genes ◽  
Genome Draft ◽  
Genomic Scale ◽  
Eukaryotic Organisms ◽  
Eukaryotic Genomes

Alternative splicing (AS) is a common posttranscriptional process in eukaryotic organisms, by which multiple distinct functional transcripts are produced from a single gene. The release of the human genome draft revealed a much smaller number of genes than anticipated. Because of its potential role in expanding protein diversity, interest in alternative splicing has been increasing over the last decade. Although recent studies have shown that 94% human multiexon genes undergo AS, evolution of AS and thus its potential role in functional innovation in eukaryotic genomes remain largely unexplored. Here we review available evidence regarding the evolution of AS prevalence and functional role. In addition we stress the need to correct for the strong effect of transcript coverage in AS detection and set out a strategy to ultimately elucidate the extent of the role of AS in functional innovation on a genomic scale.

scholarly journals Blood Relatives: Splicing Mechanisms underlying Erythropoiesis in Health and Disease

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 1364 ◽  
Author(s):  
Kirsten A. Reimer ◽  
Karla M. Neugebauer
Keyword(s):  
Alternative Splicing ◽  
Gene Editing ◽  
Intron Retention ◽  
Mrna Splicing ◽  
Globin Mrna ◽  
Disease Treatment ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells ◽  
Health And Disease

During erythropoiesis, hematopoietic stem and progenitor cells transition to erythroblasts en route to terminal differentiation into enucleated red blood cells. Transcriptome-wide changes underlie distinct morphological and functional characteristics at each cell division during this process. Many studies of gene expression have historically been carried out in erythroblasts, and the biogenesis of β-globin mRNA—the most highly expressed transcript in erythroblasts—was the focus of many seminal studies on the mechanisms of pre-mRNA splicing. We now understand that pre-mRNA splicing plays an important role in shaping the transcriptome of developing erythroblasts. Recent advances have provided insight into the role of alternative splicing and intron retention as important regulatory mechanisms of erythropoiesis. However, dysregulation of splicing during erythropoiesis is also a cause of several hematological diseases, including β-thalassemia and myelodysplastic syndromes. With a growing understanding of the role that splicing plays in these diseases, we are well poised to develop gene-editing treatments. In this review, we focus on changes in the developing erythroblast transcriptome caused by alternative splicing, the molecular basis of splicing-related blood diseases, and therapeutic advances in disease treatment using CRISPR/Cas9 gene editing.

scholarly journals Transcriptional changes and the role of ONECUT1 in hPSC pancreatic differentiation

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Sandra Heller ◽  
Zhijian Li ◽  
Qiong Lin ◽  
Ryan Geusz ◽  
Markus Breunig ◽  
...  
Keyword(s):  
Stem Cells ◽  
Transcription Factors ◽  
Pluripotent Stem Cells ◽  
Human Pluripotent Stem Cells ◽  
Model Systems ◽  
Open Chromatin ◽  
Sequencing Data ◽  
Pancreatic Development ◽  
Pancreatic Differentiation

AbstractCell type specification during pancreatic development is tightly controlled by a transcriptional and epigenetic network. The precise role of most transcription factors, however, has been only described in mice. To convey such concepts to human pancreatic development, alternative model systems such as pancreatic in vitro differentiation of human pluripotent stem cells can be employed. Here, we analyzed stage-specific RNA-, ChIP-, and ATAC-sequencing data to dissect transcriptional and regulatory mechanisms during pancreatic development. Transcriptome and open chromatin maps of pancreatic differentiation from human pluripotent stem cells provide a stage-specific pattern of known pancreatic transcription factors and indicate ONECUT1 as a crucial fate regulator in pancreas progenitors. Moreover, our data suggest that ONECUT1 is also involved in preparing pancreatic progenitors for later endocrine specification. The dissection of the transcriptional and regulatory circuitry revealed an important role for ONECUT1 within such network and will serve as resource to study human development and disease.

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