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Loss of RREB1 in pa...
Loss of RREB1 in pancreatic beta cells reduces cellular insulin content and affects endocrine cell gene expression
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- Mattis, Katia K (author)
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.
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- Krentz, Nicole A J (author)
- Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
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- Metzendorf, Christoph (author)
- Uppsala universitet,Institutionen för immunologi, genetik och patologi,Science for Life Laboratory, SciLifeLab
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- Abaitua, Fernando (author)
- Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
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- Spigelman, Aliya F (author)
- Department of Pharmacology, University of Alberta, Edmonton, AB, Canada.
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- Sun, Han (author)
- Division of Endocrinology, Department of Pediatrics, Stanford School of Medicine, Stanford University, Stanford, CA, USA.
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- Ikle, Jennifer M (author)
- Division of Endocrinology, Department of Pediatrics, Stanford School of Medicine, Stanford University, Stanford, CA, USA.
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- Thaman, Swaraj (author)
- Division of Endocrinology, Department of Pediatrics, Stanford School of Medicine, Stanford University, Stanford, CA, USA.
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- Rottner, Antje K (author)
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.
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- Bautista, Austin (author)
- Department of Pharmacology, University of Alberta, Edmonton, AB, Canada.
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- Mazzaferro, Eugenia (author)
- Uppsala universitet,Institutionen för immunologi, genetik och patologi,Science for Life Laboratory, SciLifeLab
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- Perez-Alcantara, Marta (author)
- Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
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- Manning Fox, Jocelyn E (author)
- Department of Pharmacology, University of Alberta, Edmonton, AB, Canada.
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- Torres, Jason M (author)
- Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
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- Wesolowska-Andersen, Agata (author)
- Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
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- Yu, Grace Z (author)
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.
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- Mahajan, Anubha (author)
- Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
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- Larsson, Anders (author)
- Uppsala universitet,Klinisk kemi
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- MacDonald, Patrick E (author)
- Department of Pharmacology, University of Alberta, Edmonton, AB, Canada.
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- Davies, Benjamin (author)
- Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
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- den Hoed, Marcel, 1980- (author)
- Uppsala universitet,Institutionen för immunologi, genetik och patologi,Science for Life Laboratory, SciLifeLab
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- Gloyn, Anna L (author)
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.
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Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK. (creator_code:org_t)
- 2023-01-12
- 2023
- English.
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In: Diabetologia. - : Springer Nature. - 0012-186X .- 1432-0428. ; 66:4, s. 674-694
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Abstract
Subject headings
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- AIMS/HYPOTHESIS: Genome-wide studies have uncovered multiple independent signals at the RREB1 locus associated with altered type 2 diabetes risk and related glycaemic traits. However, little is known about the function of the zinc finger transcription factor Ras-responsive element binding protein 1 (RREB1) in glucose homeostasis or how changes in its expression and/or function influence diabetes risk.METHODS: A zebrafish model lacking rreb1a and rreb1b was used to study the effect of RREB1 loss in vivo. Using transcriptomic and cellular phenotyping of a human beta cell model (EndoC-βH1) and human induced pluripotent stem cell (hiPSC)-derived beta-like cells, we investigated how loss of RREB1 expression and activity affects pancreatic endocrine cell development and function. Ex vivo measurements of human islet function were performed in donor islets from carriers of RREB1 type 2 diabetes risk alleles.RESULTS: CRISPR/Cas9-mediated loss of rreb1a and rreb1b function in zebrafish supports an in vivo role for the transcription factor in beta cell mass, beta cell insulin expression and glucose levels. Loss of RREB1 also reduced insulin gene expression and cellular insulin content in EndoC-βH1 cells and impaired insulin secretion under prolonged stimulation. Transcriptomic analysis of RREB1 knockdown and knockout EndoC-βH1 cells supports RREB1 as a novel regulator of genes involved in insulin secretion. In vitro differentiation of RREB1KO/KO hiPSCs revealed dysregulation of pro-endocrine cell genes, including RFX family members, suggesting that RREB1 also regulates genes involved in endocrine cell development. Human donor islets from carriers of type 2 diabetes risk alleles in RREB1 have altered glucose-stimulated insulin secretion ex vivo, consistent with a role for RREB1 in regulating islet cell function.CONCLUSIONS/INTERPRETATION: Together, our results indicate that RREB1 regulates beta cell function by transcriptionally regulating the expression of genes involved in beta cell development and function.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)
Keyword
- Beta cell
- CRISPR/Cas9
- Diabetes
- Differentiation
- Human genetics
- Pancreatic islet
- RREB1
- Stem cell
- Transcription factor
- Zebrafish
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Mattis, Katia K
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Krentz, Nicole A ...
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Metzendorf, Chri ...
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Abaitua, Fernand ...
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Spigelman, Aliya ...
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Sun, Han
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show more...
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Ikle, Jennifer M
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Thaman, Swaraj
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Rottner, Antje K
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Bautista, Austin
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Mazzaferro, Euge ...
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Perez-Alcantara, ...
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Manning Fox, Joc ...
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Torres, Jason M
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Wesolowska-Ander ...
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Yu, Grace Z
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Mahajan, Anubha
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Larsson, Anders
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MacDonald, Patri ...
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Davies, Benjamin
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den Hoed, Marcel ...
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Gloyn, Anna L
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Endocrinology an ...
- Articles in the publication
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Diabetologia
- By the university
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Uppsala University