Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.822199
Title: Loss of β-cell identity in diabetes : significance of miR-7-mediated chromatin remodelling
Author: von Ohlen, Yorrick
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2019
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Abstract:
Type 2 diabetes (T2D) affects 10% of the adult global population and is a multifactorial disease characterised by insulin resistance of peripheral organs. Insulin resistance results eventually in failure of pancreatic β-cells and subsequent apoptosis. Recent research revealed that β-cell dedifferentiation is contributing to decreasing their function in T2D. Dedifferentiated β-cells express atypical non-β-cell hormones, suggesting transdifferentiation into other cells. Our group previously showed that miR-7 levels are increased in T2D. Upregulation of miR-7a2 in β-cells of mice resulted in a diabetic phenotype and loss of key β-cell identity markers. The aims of this study were to 1) investigate if miR-7a2 triggers the dedifferentiation of β-cells, 2) identify messenger RNA (mRNA) targets of miR-7 which contribute to induce β-cell dedifferentiation in T2D, and 3) assess how miR-7 targets impact on the functional identity of mature β-cells. Our results showed that elevated miR-7a2 levels impair β-cell identity in mouse and human, accompanied by the occurrence of polyhormonal β-cells. Furthermore, we demonstrated that miR-7a2 is a regulator of the chromatin remodelling mSWI/SNF complexes, through repression of the catalytic ATPase subunit Brahma-related gene 1 (Brg1) both in vitro and in vivo. Additionally, we revealed that miR-7a2 represses the expression of BAF60A, a regulatory subunit of mSWI/SNF complexes. β-cell-specific miR-7a2 overexpression in mice resulted in the closure of chromatin around genes involved in maintaining β-cell identity. Those regions overlapped with binding sites of β-cell specific transcription factors (TF). Knockdown of Brg1 in β-cell lines and β-cell specific Brg1 deletion in mice resulted in the loss of β-cell identity as revealed by the downregulation of β-cell markers, reduction of pancreatic islet insulin protein content and an impairment in glucose stimulated insulin secretion (GSIS).
Supervisor: Latreille, Mathieu Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.822199  DOI:
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