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The RNA-binding profile of the splicing factor SRSF6 in immortalized human pancreatic β-cells

In pancreatic β-cells, the expression of the splicing factor SRSF6 is regulated by GLIS3, a transcription factor encoded by a diabetes susceptibility gene. SRSF6 down-regulation promotes β-cell demise through splicing dysregulation of central genes for β-cells function and survival, but how RNAs are...

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Autores principales: Alvelos, Maria Inês, Brüggemann, Mirko, Sutandy, FX Reymond, Juan-Mateu, Jonàs, Colli, Maikel Luis, Busch, Anke, Lopes, Miguel, Castela, Ângela, Aartsma-Rus, Annemieke, König, Julian, Zarnack, Kathi, Eizirik, Décio L
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Life Science Alliance LLC 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772782/
https://www.ncbi.nlm.nih.gov/pubmed/33376132
http://dx.doi.org/10.26508/lsa.202000825
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author Alvelos, Maria Inês
Brüggemann, Mirko
Sutandy, FX Reymond
Juan-Mateu, Jonàs
Colli, Maikel Luis
Busch, Anke
Lopes, Miguel
Castela, Ângela
Aartsma-Rus, Annemieke
König, Julian
Zarnack, Kathi
Eizirik, Décio L
author_facet Alvelos, Maria Inês
Brüggemann, Mirko
Sutandy, FX Reymond
Juan-Mateu, Jonàs
Colli, Maikel Luis
Busch, Anke
Lopes, Miguel
Castela, Ângela
Aartsma-Rus, Annemieke
König, Julian
Zarnack, Kathi
Eizirik, Décio L
author_sort Alvelos, Maria Inês
collection PubMed
description In pancreatic β-cells, the expression of the splicing factor SRSF6 is regulated by GLIS3, a transcription factor encoded by a diabetes susceptibility gene. SRSF6 down-regulation promotes β-cell demise through splicing dysregulation of central genes for β-cells function and survival, but how RNAs are targeted by SRSF6 remains poorly understood. Here, we define the SRSF6 binding landscape in the human pancreatic β-cell line EndoC-βH1 by integrating individual-nucleotide resolution UV cross-linking and immunoprecipitation (iCLIP) under basal conditions with RNA sequencing after SRSF6 knockdown. We detect thousands of SRSF6 bindings sites in coding sequences. Motif analyses suggest that SRSF6 specifically recognizes a purine-rich consensus motif consisting of GAA triplets and that the number of contiguous GAA triplets correlates with increasing binding site strength. The SRSF6 positioning determines the splicing fate. In line with its role in β-cell function, we identify SRSF6 binding sites on regulated exons in several diabetes susceptibility genes. In a proof-of-principle, the splicing of the susceptibility gene LMO7 is modulated by antisense oligonucleotides. Our present study unveils the splicing regulatory landscape of SRSF6 in immortalized human pancreatic β-cells.
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spelling pubmed-77727822021-01-12 The RNA-binding profile of the splicing factor SRSF6 in immortalized human pancreatic β-cells Alvelos, Maria Inês Brüggemann, Mirko Sutandy, FX Reymond Juan-Mateu, Jonàs Colli, Maikel Luis Busch, Anke Lopes, Miguel Castela, Ângela Aartsma-Rus, Annemieke König, Julian Zarnack, Kathi Eizirik, Décio L Life Sci Alliance Research Articles In pancreatic β-cells, the expression of the splicing factor SRSF6 is regulated by GLIS3, a transcription factor encoded by a diabetes susceptibility gene. SRSF6 down-regulation promotes β-cell demise through splicing dysregulation of central genes for β-cells function and survival, but how RNAs are targeted by SRSF6 remains poorly understood. Here, we define the SRSF6 binding landscape in the human pancreatic β-cell line EndoC-βH1 by integrating individual-nucleotide resolution UV cross-linking and immunoprecipitation (iCLIP) under basal conditions with RNA sequencing after SRSF6 knockdown. We detect thousands of SRSF6 bindings sites in coding sequences. Motif analyses suggest that SRSF6 specifically recognizes a purine-rich consensus motif consisting of GAA triplets and that the number of contiguous GAA triplets correlates with increasing binding site strength. The SRSF6 positioning determines the splicing fate. In line with its role in β-cell function, we identify SRSF6 binding sites on regulated exons in several diabetes susceptibility genes. In a proof-of-principle, the splicing of the susceptibility gene LMO7 is modulated by antisense oligonucleotides. Our present study unveils the splicing regulatory landscape of SRSF6 in immortalized human pancreatic β-cells. Life Science Alliance LLC 2020-12-29 /pmc/articles/PMC7772782/ /pubmed/33376132 http://dx.doi.org/10.26508/lsa.202000825 Text en © 2020 Alvelos et al. https://creativecommons.org/licenses/by/4.0/This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Articles
Alvelos, Maria Inês
Brüggemann, Mirko
Sutandy, FX Reymond
Juan-Mateu, Jonàs
Colli, Maikel Luis
Busch, Anke
Lopes, Miguel
Castela, Ângela
Aartsma-Rus, Annemieke
König, Julian
Zarnack, Kathi
Eizirik, Décio L
The RNA-binding profile of the splicing factor SRSF6 in immortalized human pancreatic β-cells
title The RNA-binding profile of the splicing factor SRSF6 in immortalized human pancreatic β-cells
title_full The RNA-binding profile of the splicing factor SRSF6 in immortalized human pancreatic β-cells
title_fullStr The RNA-binding profile of the splicing factor SRSF6 in immortalized human pancreatic β-cells
title_full_unstemmed The RNA-binding profile of the splicing factor SRSF6 in immortalized human pancreatic β-cells
title_short The RNA-binding profile of the splicing factor SRSF6 in immortalized human pancreatic β-cells
title_sort rna-binding profile of the splicing factor srsf6 in immortalized human pancreatic β-cells
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772782/
https://www.ncbi.nlm.nih.gov/pubmed/33376132
http://dx.doi.org/10.26508/lsa.202000825
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