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HMG20A (also known as iBRAF) is a chromatin factor involved in neuronal differentiation and maturation. Recently small nucleotide polymorphisms (SNPs) in the  HMG20A  gene have been linked to type 2 diabetes mellitus (T2DM) yet neither expression nor function of this T2DM candidate gene in islets is known. Herein we demonstrate that  HMG20A  is expressed in both human and mouse islets and that levels are decreased in islets of T2DM donors as compared to islets from non-diabetic donors. In vitro studies in mouse and human islets demonstrated that glucose transiently increased  HMG20A  transcript levels, a result also observed in islets of gestating mice. In contrast, HMG20A expression was not altered in islets from diet-induced obese and pre-diabetic mice. The T2DM-associated rs7119 SNP, located in the 3′ UTR of the  HMG20A  transcript reduced the luciferase activity of a reporter construct in the human beta 1.1E7 cell line. Depletion of  Hmg20a  in the rat INS-1E cell line resulted in decreased expression levels of its neuronal target gene  NeuroD  whereas  Rest  and  Pax4  were increased. Chromatin immunoprecipitation confirmed the interaction of HMG20A with the  Pax4  gene promoter. Expression levels of  Mafa ,  Glucokinase , and  Insulin  were also inhibited. Furthermore, glucose-induced insulin secretion was blunted in HMG20A-depleted islets. In summary, our data demonstrate that HMG20A expression in islet is essential for metabolism-insulin secretion coupling via the coordinated regulation of key islet-enriched genes such as  NeuroD  and  Mafa  and that depletion induces expression of genes such as  Pax4  and  Rest  implicated in beta cell de-differentiation. More importantly we assign to the T2DM-linked rs7119 SNP the functional consequence of reducing  HMG20A  expression likely translating to impaired beta cell mature function.

The type 2 diabetes-associated HMG20A gene is mandatory for islet beta cell functional maturity