Regulation of HNF1A in human pancreatic β-cells

Abstract

HNF1A is a transcription factor important for normal pancreatic β-cell function. Heterozygous mutations in HNF1A result in monogenic diabetes. Furthermore, rare and common variants in HNF1A influence Type 2 diabetes risk. Little is known about how this gene is regulated. Since monogenic diabetes is a result of haploinsufficiency, understanding how HNF1A is regulated in β-cells and being able to specifically enhance its expression could lead to the development of treatments that correct the underlying defect in patients with HNF1A-deficient diabetes. Here, I performed two high-throughput screening methods, a chemical compound screen and a CRISPR/Cas9 regulatory screen, to identify upstream regulators of HNF1A in human pancreatic β-cells. The compound screen successfully identified several molecules capable of increasing the levels of HNF1A in β-cells. The CRISPR/Cas9 regulatory screen successfully identified regulatory elements, both proximal and distal, that contribute to the regulation of HNF1A. Both screens complemented each other in identifying upstream regulators of HNF1A. These results provide new insights into the molecular mechanisms involved in the regulation of HNF1A and constitute a step towards the development of personalised therapies.