scholarly journals Long Non-Coding RNA Expression Levels Modulate Cell-Type Specific Splicing Patterns by Altering Their Interaction Landscape with RNA-Binding Proteins

2019 ◽  
Author(s):  
Felipe Wendt Porto ◽  
Swapna Vidhur Daulatabad ◽  
Sarath Chandra Janga
Keyword(s):  
Alternative Splicing ◽  
Rna Binding ◽  
Cell Type ◽  
Non Coding Rna ◽  
Specific Manner ◽  
Alternatively Spliced ◽  
A Cell ◽  
Cell Type Specific ◽  
Rna Interaction ◽  
Long Non Coding Rna

Background: Recent developments in our understanding of the interactions between long non-coding RNA (lncRNA) and cellular components have improved treatment approaches for various human diseases including cancer, vascular diseases, and neurological diseases. Although investigation of specific lncRNAs revealed their role in the metabolism of cellular RNA, our understanding of their contribution to post-transcriptional regulation is relatively limited. In this study, we explore the role of lncRNAs in modulating alternative splicing and their impact on downstream protein-RNA interaction networks. Results: Analysis of alternative splicing events across 39 lncRNA wildtype and knockout RNA-sequencing datasets from three human cell lines: HeLa (Cervical Cancer), K562 (Myeloid Leukemia), and U87 (Glioblastoma), resulted in high confidence (fdr < 0.01) identification of 4432 skipped exon events and 2474 retained intron events, implicating 759 genes to be impacted at post-transcriptional level due to the loss of lncRNAs. We observed that a majority of the alternatively spliced genes in a lncRNA knockout were specific to the cell type, in agreement with the finding that genes affected by alternative splicing also displayed enriched functions in a cell type specific manner. To understand the mechanism behind this cell-type specific alternative splicing patterns, we analyzed RNA binding protein (RBP)-RNA interaction profiles across the spliced regions. Conclusions: Despite limited RBP binding data across cell lines, alternatively spliced events detected in lncRNA perturbation experiments were associated with RBPs binding in proximal intron-exon junctions, in a cell type specific manner. The cellular functions affected by alternative splicing were also affected in a cell type specific manner. Based on the RBP binding profiles in HeLa and K562 cells, we hypothesize that several lncRNAs are likely to exhibit a sponge effect in disease contexts, resulting in the functional disruption of RBPs due to altered titration of the RBPs from their target loci. We propose that such lncRNA sponges can extensively rewire the post-transcriptional gene regulatory networks by altering the protein-RNA interaction landscape in a cell-type specific manner.

scholarly journals Long Non-Coding RNA Expression Levels Modulate Cell-Type-Specific Splicing Patterns by Altering Their Interaction Landscape with RNA-Binding Proteins

Genes ◽  
2019 ◽  
Vol 10 (8) ◽  
pp. 593 ◽  
Author(s):  
Felipe Wendt Porto ◽  
Swapna Vidhur Daulatabad ◽  
Sarath Chandra Janga
Keyword(s):  
Alternative Splicing ◽  
Cell Lines ◽  
Rna Binding ◽  
Cell Type ◽  
Specific Manner ◽  
Alternatively Spliced ◽  
A Cell ◽  
Specific Alternative ◽  
Cell Type Specific ◽  
Rna Interaction

Recent developments in our understanding of the interactions between long non-coding RNAs (lncRNAs) and cellular components have improved treatment approaches for various human diseases including cancer, vascular diseases, and neurological diseases. Although investigation of specific lncRNAs revealed their role in the metabolism of cellular RNA, our understanding of their contribution to post-transcriptional regulation is relatively limited. In this study, we explore the role of lncRNAs in modulating alternative splicing and their impact on downstream protein–RNA interaction networks. Analysis of alternative splicing events across 39 lncRNA knockdown and wildtype RNA-sequencing datasets from three human cell lines—HeLa (cervical cancer), K562 (myeloid leukemia), and U87 (glioblastoma)—resulted in the high-confidence (false discovery rate (fdr) < 0.01) identification of 11,630 skipped exon events and 5895 retained intron events, implicating 759 genes to be impacted at the post-transcriptional level due to the loss of lncRNAs. We observed that a majority of the alternatively spliced genes in a lncRNA knockdown were specific to the cell type. In tandem, the functions annotated to the genes affected by alternative splicing across each lncRNA knockdown also displayed cell-type specificity. To understand the mechanism behind this cell-type-specific alternative splicing pattern, we analyzed RNA-binding protein (RBP)–RNA interaction profiles across the spliced regions in order to observe cell-type-specific alternative splice event RBP binding preference. Despite limited RBP binding data across cell lines, alternatively spliced events detected in lncRNA perturbation experiments were associated with RBPs binding in proximal intron–exon junctions in a cell-type-specific manner. The cellular functions affected by alternative splicing were also affected in a cell-type-specific manner. Based on the RBP binding profiles in HeLa and K562 cells, we hypothesize that several lncRNAs are likely to exhibit a sponge effect in disease contexts, resulting in the functional disruption of RBPs and their downstream functions. We propose that such lncRNA sponges can extensively rewire post-transcriptional gene regulatory networks by altering the protein–RNA interaction landscape in a cell-type-specific manner.

scholarly journals Long non-coding RNA expression levels modulate cell-type specific splicing patterns by altering their interaction landscape with RNA-binding proteins

2019 ◽  
Author(s):  
Felipe Wendt Porto ◽  
Swapna Vidhur Daulatabad ◽  
Sarath Chandra Janga
Keyword(s):  
Alternative Splicing ◽  
Rna Binding ◽  
Cell Type ◽  
Specific Manner ◽  
Alternatively Spliced ◽  
A Cell ◽  
Specific Alternative ◽  
Cell Type Specific ◽  
Rna Interaction ◽  
Splicing Patterns

AbstractBackgroundRecent developments in our understanding of the interactions between long non-coding RNAs (lncRNAs) and cellular components have improved treatment approaches for various human diseases including cancer, vascular diseases, and neurological diseases. Although investigation of specific lncRNAs revealed their role in the metabolism of cellular RNA, our understanding of their contribution to post-transcriptional regulation is relatively limited. In this study, we explore the role of lncRNAs in modulating alternative splicing and their impact on downstream protein-RNA interaction networks.ResultsAnalysis of alternative splicing events across 39 lncRNA knockdown and wildtype RNA-sequencing datasets from three human cell lines: HeLa (Cervical Cancer), K562 (Myeloid Leukemia), and U87 (Glioblastoma), resulted in high confidence (fdr < 0.01) identification of 11630 skipped exon events and 5895 retained intron events, implicating 759 genes to be impacted at post-transcriptional level due to the loss of lncRNAs. We observed that a majority of the alternatively spliced genes in a lncRNA knockdown were specific to the cell type, in tandem, the functions annotated to the genes affected by alternative splicing across each lncRNA knockdown also displayed cell type specificity. To understand the mechanism behind this cell-type specific alternative splicing patterns, we analyzed RNA binding protein (RBP)-RNA interaction profiles across the spliced regions, to observe cell type specific alternative splice event RBP binding preference.ConclusionsDespite limited RBP binding data across cell lines, alternatively spliced events detected in lncRNA perturbation experiments were associated with RBPs binding in proximal intron-exon junctions, in a cell type specific manner. The cellular functions affected by alternative splicing were also affected in a cell type specific manner. Based on the RBP binding profiles in HeLa and K562 cells, we hypothesize that several lncRNAs are likely to exhibit a sponge effect in disease contexts, resulting in the functional disruption of RBPs, and their downstream functions. We propose that such lncRNA sponges can extensively rewire the post-transcriptional gene regulatory networks by altering the protein-RNA interaction landscape in a cell-type specific manner.

scholarly journals Epigenetic Regulation of Alternative Splicing: How LncRNAs Tailor the Message

2021 ◽  
Vol 7 (1) ◽  
pp. 21
Author(s):  
Giuseppina Pisignano ◽  
Michael Ladomery
Keyword(s):  
Alternative Splicing ◽  
Epigenetic Regulation ◽  
Cell Type ◽  
Splice Isoforms ◽  
Cellular Processes ◽  
Specific Manner ◽  
Protein Functions ◽  
Alternatively Spliced ◽  
A Cell ◽  
Non Coding Rnas

Alternative splicing is a highly fine-tuned regulated process and one of the main drivers of proteomic diversity across eukaryotes. The vast majority of human multi-exon genes is alternatively spliced in a cell type- and tissue-specific manner, and defects in alternative splicing can dramatically alter RNA and protein functions and lead to disease. The eukaryotic genome is also intensively transcribed into long and short non-coding RNAs which account for up to 90% of the entire transcriptome. Over the years, lncRNAs have received considerable attention as important players in the regulation of cellular processes including alternative splicing. In this review, we focus on recent discoveries that show how lncRNAs contribute significantly to the regulation of alternative splicing and explore how they are able to shape the expression of a diverse set of splice isoforms through several mechanisms. With the increasing number of lncRNAs being discovered and characterized, the contribution of lncRNAs to the regulation of alternative splicing is likely to grow significantly.

Elements regulating an alternatively spliced exon of the rat fibronectin gene

1993 ◽  
Vol 13 (9) ◽  
pp. 5301-5314 ◽  
Author(s):  
G S Huh ◽  
R O Hynes
Keyword(s):  
Splice Sites ◽  
Cell Type ◽  
Long Distance ◽  
Sequence Elements ◽  
Alternatively Spliced ◽  
A Cell ◽  
Cell Type Specific ◽  
Alternatively Spliced Exons

We have investigated the regulation of splicing of one of the alternatively spliced exons in the rat fibronectin gene, the EIIIB exon. This 273-nucleotide exon is excluded by some cells and included to various degrees by others. We find that EIIIB is intrinsically poorly spliced and that both its exon sequences and its splice sites contribute to its poor recognition. Therefore, cells which recognize the EIIIB exon must have mechanisms for improving its splicing. Furthermore, in order for EIIB to be regulated, a balance must exist between the EIIIB splice sites and those of its flanking exons. Although the intron upstream of EIIIB does not appear to play a role in the recognition of EIIIB for splicing, the intron downstream contains sequence elements which can promote EIIIB recognition in a cell-type-specific fashion. These elements are located an unusually long distance from the exon that they regulate, more than 518 nucleotides downstream from EIIIB, and may represent a novel mode of exon regulation.

scholarly journals Rel Induces Interferon Regulatory Factor 4 (IRF-4) Expression in Lymphocytes

2000 ◽  
Vol 191 (8) ◽  
pp. 1281-1292 ◽  
Author(s):  
Raelene J. Grumont ◽  
Steve Gerondakis
Keyword(s):  
Gene Expression ◽  
Cell Proliferation ◽  
Nuclear Factor Κb ◽  
Wild Type ◽  
Cell Type ◽  
Regulatory Factor ◽  
Specific Manner ◽  
A Cell ◽  
Cell Type Specific ◽  
Interferon Regulatory Factor 4

In lymphocytes, the Rel transcription factor is essential in establishing a pattern of gene expression that promotes cell proliferation, survival, and differentiation. Here we show that mitogen-induced expression of interferon (IFN) regulatory factor 4 (IRF-4), a lymphoid-specific member of the IFN family of transcription factors, is Rel dependent. Consistent with IRF-4 functioning as a repressor of IFN-induced gene expression, the absence of IRF-4 expression in c-rel−/− B cells coincided with a greater sensitivity of these cells to the antiproliferative activity of IFNs. In turn, enforced expression of an IRF-4 transgene restored IFN modulated c-rel−/− B cell proliferation to that of wild-type cells. This cross-regulation between two different signaling pathways represents a novel mechanism that Rel/nuclear factor κB can repress the transcription of IFN-regulated genes in a cell type–specific manner.

PLAG1 enhances the stemness profiles of acinar cells in normal human salivary glands in a cell type-specific manner

2020 ◽  
Vol 62 (1) ◽  
pp. 99-106 ◽  
Author(s):  
Yuriko Goto ◽  
Miho Ibi ◽  
Hirotaka Sato ◽  
Junichi Tanaka ◽  
Rika Yasuhara ◽  
...  
Keyword(s):  
Salivary Glands ◽  
Acinar Cells ◽  
Cell Type ◽  
Specific Manner ◽  
A Cell ◽  
Normal Human ◽  
Cell Type Specific

Abstract LB-028: Cell density sensing alters TGF-beta signaling in a cell type-specific manner, independent from Hippo pathway activation

2015 ◽  
Author(s):  
Flore Nallet-Staub ◽  
Xueqian Yin ◽  
Cristèle Gilbert ◽  
Véronique Marsaud ◽  
Saber Ben Mimoun ◽  
...  
Keyword(s):  
Cell Density ◽  
Hippo Pathway ◽  
Tgf Beta ◽  
Cell Type ◽  
Pathway Activation ◽  
Specific Manner ◽  
A Cell ◽  
Cell Type Specific
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