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

Abstract

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.

Insulin promoter in human pancreatic β cells contacts diabetes susceptibility loci and regulates genes affecting insulin metabolism

“…Among the 34 T2D susceptibility loci listed by Bonnefond and Froguel (11) that affect insulin secretion or islet function, we find seven that contact INS, indicating that there is enrichment of those loci in the contact region (χ 2 test, P = 0.003). A recent report showed that the expression levels of one of the loci, the HMG20A gene, are decreased in islets from T2D donors compared with islets from nondiabetic donors (29). The enrichment of T1D susceptibility loci is more significant, as the HLA loci resides inside the 4C contact regions.…”

Phenotypic and genotypic differences between Indian and Scandinavian women with gestational diabetes mellitus

“…The Proline-Serine-Threonine Phosphatase Interacting Protein 1 (PSTPIP1) gene is a tyrosine phosphatase that inhibits T-cell activation upon T-cell receptor (TCR) and CD28 engagement, regardless of CD2 co-stimulation [37]. The HMG20A gene had higher expression in islets than in muscle and adipose tissue [38], and a transient increase in expression levels was observed upon glucose stimulation [38]. HMG20A has been reported to be down-regulated in T2D and T1D islets, and knockdown of HMG20A decreased expression of NEUROD, INS and GK with an accompanying impairment in GSIS [38].…”

“…The HMG20A gene had higher expression in islets than in muscle and adipose tissue [38], and a transient increase in expression levels was observed upon glucose stimulation [38]. HMG20A has been reported to be down-regulated in T2D and T1D islets, and knockdown of HMG20A decreased expression of NEUROD, INS and GK with an accompanying impairment in GSIS [38]. Therefore, this SNP could through its eQTL effect on HMG20A expression in islets be a plausible candidate gene for GDM.…”

Effects of variants of 50 genes on diabetes risk among the Chinese population born in the early 1960s

“…Diabetes is caused by a progressive loss of β‐cell insulin secretion frequently against a background of insulin resistance, or autoimmune β‐cell destruction, usually leading to absolute insulin deficiency . Among the 50 SNPs included in this study, most loci exerted their primary effects on disease risk through deficient insulin secretion, some loci were related to insulin resistance or insulin sensibility, and some loci may be the adapter or receptor that can indirectly affect insulin sensitivity or increase diabetes susceptibility …”

“…22,23 Among the 50 SNPs included in this study, most loci exerted their primary effects on disease risk through deficient insulin secretion, some loci were related to insulin resistance or insulin sensibility, and some loci may be the adapter or receptor that can indirectly affect insulin sensitivity or increase diabetes susceptibility. 8,10,28,32,[36][37][38][39][40][41][42][43][44] Among the susceptibility loci examined herein, we confirmed significant evidence for an association with diabetes risk for 10 loci in the Chinese population in the following genes: cyclindependentkinase 5 regulatory subunit associated protein 1 (CDKAL1) (rs10946398), adaptorrelated protein complex 3 subunit sigma 2 (AP3S2) (rs2028299), SREBF chaperone (SCAP) (rs4858889), RAS guanyl releasing protein 1 (RASGRP1) (rs7403531), Gprotein-coupled receptor kinase 5 (GRK5) (rs10886471), diacylglycerol kinase beta/transmembrane protein 195 (DGKB/TMEM195) (rs2191349), zinc finger AN1-type containing 3 (ZFAND3) (rs9470794), kelchdomain containing 5 (KLHDC5) (rs10842994), melatonin receptor 1B (MTNR1B) (rs10830963), and ankyrin1 (ANK1) (rs516946). Previous studies have identified an association between diabetes risk and SNPs for CDKAL1 in European Americans, African Americans, UK samples, Indians, Korean, and Chinese, 33,[45][46][47][48][49] making CDKAL1 one of the most highly replicated genes identified.…”