Abstract
The high-mobility group AT-hook 1 (HMGA1) protein is a nuclear architectural factor that can organize chromatin structures. It regulates gene expression by controlling the formation of stereospecific multiprotein complexes called “enhanceosomes” on the AT-rich regions of target gene promoters. Previously, we reported that defects in HMGA1 caused decreased insulin receptor expression and increased susceptibility to type 2 diabetes mellitus in humans and mice. Interestingly, mice with disrupted HMGA1 gene had significantly smaller islets and decreased insulin content in their pancreata, suggesting that HMGA1 may have a direct role in insulin transcription and secretion. Herein, we investigate the regulatory roles of HMGA1 in insulin transcription. We provide evidence that HMGA1 physically interacts with PDX-1 and MafA, two critical transcription factors for insulin gene expression and beta-cell function, both in vitro and in vivo. We then show that the overexpression of HMGA1 significantly improves the transactivating activity of PDX-1 and MafA on human and mouse insulin promoters, while HMGA1 knockdown considerably decreased this transactivating activity. Lastly, we demonstrate that high glucose stimulus significantly increases the binding of HMGA1 to the insulin (INS) gene promoter, suggesting that HMGA1 may act as a glucose-sensitive element controlling the transcription of the INS gene. Together, our findings provide evidence that HMGA1, by regulating PDX-1- and MafA-induced transactivation of the INS gene promoter, plays a critical role in pancreatic beta-cell function and insulin production.
Highlights
Production and secretion of insulin from beta cells of the pancreas maintain glucose homeostasis in vertebrates
We further showed that binding of pancreatic and duodenal homeobox factor-1 (PDX-1) to the INS gene promoter was reduced in nuclear extracts from HMGA1-deficient mice, in which PDX-1 protein expression was unaffected compared with wild-type animals [38]
With the results reported above, and in agreement with our previous findings that pancreatic insulin mRNA transcripts were reduced in HMGA1-knockout mice [38], INS mRNA levels were significantly lower in INS-1 cells in the presence of small interfering RNAs (siRNAs) directed against HMGA1, whereas mRNA abundances of PDX-1 and MafA were not altered by siRNA-induced down-regulation of HMGA1 (Figure 4C)
Summary
Production and secretion of insulin from beta cells of the pancreas maintain glucose homeostasis in vertebrates (from fish to human). Understanding beta-cell generation and insulin production/secretion holds keys to understand and potentially cure diabetes. Insulin production in beta cells is controlled at both transcriptional and translational levels [3]. High glucose upregulates both insulin transcription and preproinsulin translation. To this end, glucose regulates proinsulin translation by altering the phosphorylation status of eukaryotic initiation factor 2α [4], while it promotes insulin transcription by activation of several beta-cell specific transcription factors [5]. Direct connections between high glucose and activation of beta-cell transcription factors have not been established
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