ISL1 controls pancreatic alpha cell fate and beta cell maturation
Abstract 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 functi...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-03-01
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| Series: | Cell & Bioscience |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13578-023-01003-9 |
| _version_ | 1797863422392532992 |
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| author | Romana Bohuslavova Valeria Fabriciova Laura Lebrón-Mora Jessica Malfatti Ondrej Smolik Lukas Valihrach Sarka Benesova Daniel Zucha Zuzana Berkova Frantisek Saudek Sylvia M Evans Gabriela Pavlinkova |
| author_facet | Romana Bohuslavova Valeria Fabriciova Laura Lebrón-Mora Jessica Malfatti Ondrej Smolik Lukas Valihrach Sarka Benesova Daniel Zucha Zuzana Berkova Frantisek Saudek Sylvia M Evans Gabriela Pavlinkova |
| author_sort | Romana Bohuslavova |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-04-09T22:36:25Z |
| format | Article |
| id | doaj.art-b82aec0be9b34ada9dbcc1271383d8de |
| institution | Directory Open Access Journal |
| issn | 2045-3701 |
| language | English |
| last_indexed | 2024-04-09T22:36:25Z |
| publishDate | 2023-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell & Bioscience |
| spelling | doaj.art-b82aec0be9b34ada9dbcc1271383d8de2023-03-22T12:29:51ZengBMCCell & Bioscience2045-37012023-03-0113112410.1186/s13578-023-01003-9ISL1 controls pancreatic alpha cell fate and beta cell maturationRomana Bohuslavova0Valeria Fabriciova1Laura Lebrón-Mora2Jessica Malfatti3Ondrej Smolik4Lukas Valihrach5Sarka Benesova6Daniel Zucha7Zuzana Berkova8Frantisek Saudek9Sylvia M Evans10Gabriela Pavlinkova11Laboratory of Molecular Pathogenetics, Institute of Biotechnology CASLaboratory of Molecular Pathogenetics, Institute of Biotechnology CASLaboratory of Molecular Pathogenetics, Institute of Biotechnology CASLaboratory of Molecular Pathogenetics, Institute of Biotechnology CASLaboratory of Molecular Pathogenetics, Institute of Biotechnology CASLaboratory of Gene Expression, Institute of Biotechnology CASLaboratory of Gene Expression, Institute of Biotechnology CASLaboratory of Gene Expression, Institute of Biotechnology CASLaboratory of Pancreatic Islets, Institute for Clinical and Experimental MedicineLaboratory of Pancreatic Islets, Institute for Clinical and Experimental MedicineDepartment of Pharmacology; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San DiegoLaboratory of Molecular Pathogenetics, Institute of Biotechnology CASAbstract 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.https://doi.org/10.1186/s13578-023-01003-9Pancreatic endocrine cellsEpigenetic histone modificationTranscriptomePancreas development |
| spellingShingle | Romana Bohuslavova Valeria Fabriciova Laura Lebrón-Mora Jessica Malfatti Ondrej Smolik Lukas Valihrach Sarka Benesova Daniel Zucha Zuzana Berkova Frantisek Saudek Sylvia M Evans Gabriela Pavlinkova ISL1 controls pancreatic alpha cell fate and beta cell maturation Cell & Bioscience Pancreatic endocrine cells Epigenetic histone modification Transcriptome Pancreas development |
| 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 | Pancreatic endocrine cells Epigenetic histone modification Transcriptome Pancreas development |
| url | https://doi.org/10.1186/s13578-023-01003-9 |
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