An alternative splicing switch shapes neurexin repertoires in principal neurons versus interneurons in the mouse hippocampus

The unique anatomical and functional features of principal and interneuron populations are critical for the appropriate function of neuronal circuits. Cell type-specific properties are encoded by selective gene expression programs that shape molecular repertoires and synaptic protein complexes. However, the nature of such programs, particularly for post-transcriptional regulation at the level of alternative splicing is only beginning to emerge. We here demonstrate that transcripts encoding the synaptic adhesion molecules neurexin-1,2,3 are commonly expressed in principal cells and interneurons of the mouse hippocampus but undergo highly differential, cell type-specific alternative splicing. Principal cell-specific neurexin splice isoforms depend on the RNA-binding protein Slm2. By contrast, most parvalbumin-positive (PV+) interneurons lack Slm2, express a different neurexin splice isoform and co-express the corresponding splice isoform-specific neurexin ligand Cbln4. Conditional ablation of Nrxn alternative splice insertions selectively in PV+ cells results in elevated hippocampal network activity and impairment in a learning task. Thus, PV-cell-specific alternative splicing of neurexins is critical for neuronal circuit function

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

Genes ◽

10.3390/genes10080593 ◽

2019 ◽

Vol 10 (8) ◽

pp. 593 ◽

Cited By ~ 4

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.

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

10.1101/683193 ◽

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.

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Neuronal cell-type-specific alternative splicing: A mechanism for specifying connections in the brain?

Neurogenesis ◽

10.1080/23262133.2015.1122699 ◽

2015 ◽

Vol 2 (1) ◽

pp. e1122699 ◽

Cited By ~ 2

Author(s):

Joshua Shing Shun Li ◽

Grace Ji-eun Shin ◽

S Sean Millard

Keyword(s):

Alternative Splicing ◽

Neuronal Cell ◽

Cell Type ◽

Specific Alternative ◽

Cell Type Specific ◽

The Brain

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Cell-type-specific alternative splicing in spinocerebellar ataxia type 6

Neuroscience Letters ◽

10.1016/j.neulet.2008.09.065 ◽

2008 ◽

Vol 447 (1) ◽

pp. 78-81 ◽

Cited By ~ 13

Author(s):

Taiji Tsunemi ◽

Kinya Ishikawa ◽

Honglian Jin ◽

Hidehiro Mizusawa

Keyword(s):

Alternative Splicing ◽

Spinocerebellar Ataxia ◽

Spinocerebellar Ataxia Type ◽

Cell Type ◽

Spinocerebellar Ataxia Type 6 ◽

Specific Alternative ◽

Cell Type Specific

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Dynamic Antagonism between ETR-3 and PTB Regulates Cell Type-Specific Alternative Splicing

Molecular Cell ◽

10.1016/s1097-2765(02)00479-3 ◽

2002 ◽

Vol 9 (3) ◽

pp. 649-658 ◽

Cited By ~ 125

Author(s):

Nicolas Charlet-B ◽

Gopal Singh ◽

Thomas A. Cooper ◽

Penny Logan

Keyword(s):

Alternative Splicing ◽

Cell Type ◽

Specific Alternative ◽

Cell Type Specific

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Faculty Opinions recommendation of Cell-Type-Specific Alternative Splicing Governs Cell Fate in the Developing Cerebral Cortex.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726681488.793524327 ◽

2016 ◽

Author(s):

Yoshimi Takai

Keyword(s):

Cerebral Cortex ◽

Alternative Splicing ◽

Cell Fate ◽

Cell Type ◽

Specific Alternative ◽

Cell Type Specific

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

10.20944/preprints201906.0259.v1 ◽

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.

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