SFEBES2023 Poster Presentations Metabolism, Obesity and Diabetes (70 abstracts)
Differential DNA methylation during postnatal development establishes a subpopulation of pancreatic beta cells with expression of the insulin secretion-enhancing gene, neuronatin
Vanessa Yu 1 , Fiona Yong 1,2 , Angellica Marta 1 , Sanjay Khadayate 3 , Supriyo Bhattach 4 , Keran Chen 1 , Eleni Georgiadou 1 , Nazia Parveen 4 , Lorella Marselli 5 , Carmela De Luca 5 , Mara Suleiman 5 , Chad Whilding 3 , Piero Marchetti 6 , Sangeeta Dhawan 4 , Dominic Withers 3,1 , Guy Rutter 7,1,2 & Steven Millership 1
1Imperial College London, London, United Kingdom. 2Nanyang Technological University, Singapore, Singapore. 3MRC London Institute of Medical Sciences, London, United Kingdom. 4Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope, Duarte, USA. 5University of Pisa, Pisa, Italy. 6University of Pisa, Pisa, USA. 7University of Montréal, Montréal, Canada
Subpopulations of beta cells dictate overall ‘pacing’ of insulin secretion across the islet and therefore the control of glycaemia. Functional beta cell subpopulations also exist in human islets and have an altered subtype distribution in type 2 diabetes. However, the molecular control of the establishment and maintenance of beta cell hierarchy is poorly understood. We hypothesised that the epigenome would govern this heterogeneity. We have identified a novel subpopulation of beta cells with ‘on/off’ expression of neuronatin (Nnat), a gene required for normal insulin synthesis and secretion. Beta cell heterogeneity at the level of Nnat expression is established via de novo CpG methylation at the Nnat promoter during early postnatal life. NNAT+ beta cells have a discrete transcriptome, appear to be functionally specialised for insulin production, and we have demonstrated their presence in the developing human pancreas. We therefore demonstrate that differential DNA methylation at the Nnat locus represents a novel means through which beta cell heterogeneity is established. Changes in methylation at this locus may thus contribute to a loss of heterogeneity, and defective insulin secretion, in some forms of diabetes. Furthermore, epigenome-modifying compounds may provide a way of enhancing beta cell function and the ensemble behaviour of the islet to stimulate insulin secretion.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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