HNF1α maintains pancreatic α and β cell functions in primary human islets

Mollie F. Qian; Romina J. Bevacqua; Vy M.N. Coykendall; Xiong Liu; Weichen Zhao; Charles A. Chang; Xueying Gu; Xiao-Qing Dai; Patrick E. MacDonald; Seung K. Kim

doi:10.1172/jci.insight.170884

HNF1α maintains pancreatic α and β cell functions in primary human islets

Mollie F. Qian,¹ Romina J. Bevacqua,² Vy M.N. Coykendall,² Xiong Liu,³ Weichen Zhao,² Charles A. Chang,² Xueying Gu,² Xiao-Qing Dai,³ Patrick E. MacDonald,⁴ and Seung K. Kim²

Published November 9, 2023 - More info

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Abstract

HNF1A haploinsufficiency underlies the most common form of human monogenic diabetes (HNF1A-MODY) and hypomorphic HNF1A variants confer type 2 diabetes risk, but a lack of experimental systems for interrogating mature human islets has limited our understanding of how the transcription factor HNF1α regulates adult islet function. Here, we combined conditional genetic targeting in human islet cells, RNA sequencing, chromatin mapping with Cleavage Under Targets & Release Using Nuclease (CUT&RUN), and transplantation-based assays to determine HNF1α-regulated mechanisms in adult human pancreatic α and β cells. Short hairpin RNA-mediated (shRNA) suppression of HNF1A in primary human pseudoislets led to blunted insulin output and dysregulated glucagon secretion after transplantation in mice, recapitulating phenotypes observed in diabetic patients. These deficits corresponded with altered expression of genes encoding factors critical for hormone secretion, including calcium channel subunits, ATPase transporters and extracellular matrix constituents. Additionally, HNF1A loss led to upregulation of transcriptional repressors, providing evidence for a mechanism of transcriptional de-repression through HNF1α. CUT&RUN mapping of HNF1α DNA-binding sites in primary human islets imputed a subset of HNF1α-regulated genes as direct targets. These data elucidate mechanistic links between HNF1A loss and diabetic phenotypes in mature human α and β cells.

HNF1α maintains pancreatic α and β cell functions in primary human islets

Mollie F. Qian,¹ Romina J. Bevacqua,² Vy M.N. Coykendall,² Xiong Liu,³ Weichen Zhao,² Charles A. Chang,² Xueying Gu,² Xiao-Qing Dai,³ Patrick E. MacDonald,⁴ and Seung K. Kim²

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HNF1α maintains pancreatic α and β cell functions in primary human islets

Mollie F. Qian,1 Romina J. Bevacqua,2 Vy M.N. Coykendall,2 Xiong Liu,3 Weichen Zhao,2 Charles A. Chang,2 Xueying Gu,2 Xiao-Qing Dai,3 Patrick E. MacDonald,4 and Seung K. Kim2

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Mollie F. Qian,¹ Romina J. Bevacqua,² Vy M.N. Coykendall,² Xiong Liu,³ Weichen Zhao,² Charles A. Chang,² Xueying Gu,² Xiao-Qing Dai,³ Patrick E. MacDonald,⁴ and Seung K. Kim²