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ISL1 controls pancreatic alpha cell fate and beta cell maturation

BACKGROUND: Glucose homeostasis is dependent on functional pancreatic α and ß cells. The mechanisms underlying the generation and maturation of these endocrine cells remain unclear. RESULTS: We unravel the molecular mode of action of ISL1 in controlling α cell fate and the formation of functional ß...

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Autores principales: Bohuslavova, Romana, Fabriciova, Valeria, Lebrón-Mora, Laura, Malfatti, Jessica, Smolik, Ondrej, Valihrach, Lukas, Benesova, Sarka, Zucha, Daniel, Berkova, Zuzana, Saudek, Frantisek, Evans, Sylvia M, Pavlinkova, Gabriela
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9999528/
https://www.ncbi.nlm.nih.gov/pubmed/36899442
http://dx.doi.org/10.1186/s13578-023-01003-9
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author Bohuslavova, Romana
Fabriciova, Valeria
Lebrón-Mora, Laura
Malfatti, Jessica
Smolik, Ondrej
Valihrach, Lukas
Benesova, Sarka
Zucha, Daniel
Berkova, Zuzana
Saudek, Frantisek
Evans, Sylvia M
Pavlinkova, Gabriela
author_facet Bohuslavova, Romana
Fabriciova, Valeria
Lebrón-Mora, Laura
Malfatti, Jessica
Smolik, Ondrej
Valihrach, Lukas
Benesova, Sarka
Zucha, Daniel
Berkova, Zuzana
Saudek, Frantisek
Evans, Sylvia M
Pavlinkova, Gabriela
author_sort Bohuslavova, Romana
collection PubMed
description BACKGROUND: Glucose homeostasis is dependent on functional pancreatic α and ß cells. The mechanisms underlying the generation and maturation of these endocrine cells remain unclear. RESULTS: We unravel the molecular mode of action of ISL1 in controlling α cell fate and the formation of functional ß cells in the pancreas. By combining transgenic mouse models, transcriptomic and epigenomic profiling, we uncover that elimination of Isl1 results in a diabetic phenotype with a complete loss of α cells, disrupted pancreatic islet architecture, downregulation of key ß-cell regulators and maturation markers of ß cells, and an enrichment in an intermediate endocrine progenitor transcriptomic profile. CONCLUSIONS: Mechanistically, apart from the altered transcriptome of pancreatic endocrine cells, Isl1 elimination results in altered silencing H3K27me3 histone modifications in the promoter regions of genes that are essential for endocrine cell differentiation. Our results thus show that ISL1 transcriptionally and epigenetically controls α cell fate competence, and ß cell maturation, suggesting that ISL1 is a critical component for generating functional α and ß cells. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13578-023-01003-9.
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spelling pubmed-99995282023-03-11 ISL1 controls pancreatic alpha cell fate and beta cell maturation Bohuslavova, Romana Fabriciova, Valeria Lebrón-Mora, Laura Malfatti, Jessica Smolik, Ondrej Valihrach, Lukas Benesova, Sarka Zucha, Daniel Berkova, Zuzana Saudek, Frantisek Evans, Sylvia M Pavlinkova, Gabriela Cell Biosci Research BACKGROUND: Glucose homeostasis is dependent on functional pancreatic α and ß cells. The mechanisms underlying the generation and maturation of these endocrine cells remain unclear. RESULTS: We unravel the molecular mode of action of ISL1 in controlling α cell fate and the formation of functional ß cells in the pancreas. By combining transgenic mouse models, transcriptomic and epigenomic profiling, we uncover that elimination of Isl1 results in a diabetic phenotype with a complete loss of α cells, disrupted pancreatic islet architecture, downregulation of key ß-cell regulators and maturation markers of ß cells, and an enrichment in an intermediate endocrine progenitor transcriptomic profile. CONCLUSIONS: Mechanistically, apart from the altered transcriptome of pancreatic endocrine cells, Isl1 elimination results in altered silencing H3K27me3 histone modifications in the promoter regions of genes that are essential for endocrine cell differentiation. Our results thus show that ISL1 transcriptionally and epigenetically controls α cell fate competence, and ß cell maturation, suggesting that ISL1 is a critical component for generating functional α and ß cells. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13578-023-01003-9. BioMed Central 2023-03-10 /pmc/articles/PMC9999528/ /pubmed/36899442 http://dx.doi.org/10.1186/s13578-023-01003-9 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Bohuslavova, Romana
Fabriciova, Valeria
Lebrón-Mora, Laura
Malfatti, Jessica
Smolik, Ondrej
Valihrach, Lukas
Benesova, Sarka
Zucha, Daniel
Berkova, Zuzana
Saudek, Frantisek
Evans, Sylvia M
Pavlinkova, Gabriela
ISL1 controls pancreatic alpha cell fate and beta cell maturation
title ISL1 controls pancreatic alpha cell fate and beta cell maturation
title_full ISL1 controls pancreatic alpha cell fate and beta cell maturation
title_fullStr ISL1 controls pancreatic alpha cell fate and beta cell maturation
title_full_unstemmed ISL1 controls pancreatic alpha cell fate and beta cell maturation
title_short ISL1 controls pancreatic alpha cell fate and beta cell maturation
title_sort isl1 controls pancreatic alpha cell fate and beta cell maturation
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9999528/
https://www.ncbi.nlm.nih.gov/pubmed/36899442
http://dx.doi.org/10.1186/s13578-023-01003-9
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