Scientists have generated a complete map of the gene targets regulated by the transcription components HNF4A and HNF1A in human pancreatic beta cells and liver cells. Revealed within the journal Nature Communications, the research revealed widespread and tissue-specific molecular pathways regulated by HNF4A and HNF1A, two proteins that possess essential features governing the event and performance of the pancreas and liver.
Notably, the scientists recognized a number of novel gene targets in pancreatic beta cells, the cells accountable for insulin manufacturing, that will play beforehand unknown roles in regulating insulin secretion. As genetic variants in HNF4A and HNF1A are identified to trigger a uncommon type of diabetes referred to as Maturity Onset Diabetes of the Younger (MODY) and likewise affect threat for the extra widespread sort 2 diabetes, these findings present worthwhile insights into potential therapeutic targets for diabetes.
The analysis staff, led by Dr. Adrian Teo, Senior Principal Investigator at A*STAR’s Institute of Molecular and Cell Biology (IMCB), used the cutting-edge strategy of chromatin immunoprecipitation sequencing (ChIP-Seq) to map the genomic binding websites of HNF4A and HNF1A in stem cell-derived fashions of human pancreatic and liver cells, and in major human islets.
By evaluating the binding profiles throughout completely different cell varieties, they discovered that whereas these two transcription components regulate some widespread genes and processes like actin cytoskeleton group in each pancreatic beta cells and liver cells, additionally they exhibit tissue-specific binding patterns that correspond to the distinct features of every cell sort. For instance, in liver cells, HNF4A preferentially certain to genes concerned in ldl cholesterol and fatty acid metabolism.
Zooming in on the pancreatic beta cell targets, the scientists shortlisted a number of high-confidence genes straight certain and controlled by HNF4A, together with HAAO and USH1C, which haven’t been beforehand characterised in beta cells.
They confirmed that lack of HAAO or USH1C led to impaired glucose-stimulated insulin secretion in human beta cells, indicating that these genes regulate beta cell perform.
Utilizing an identical ChIP-Seq primarily based strategy, the research additionally investigated the molecular influence of a typical genetic variant in HNF4A that’s related to sort 2 diabetes threat.
The scientists discovered that this variant led to elevated binding and activation of a small variety of gene targets, suggesting a possible gain-of-function impact at particular gene areas that will affect diabetes predisposition.
“HNF4A and HNF1A are crucial diabetes genes identified to be regulating insulin secretion however their targets remained unclear,” mentioned Dr. Teo, the research’s senior writer.
“We’re excited to additional discover a few of these novel targets or pathways which can function entry factors for creating future diabetes therapies,” added Dr. Teo.
“Our research offers the group with a complete useful resource for investigating HNF4A and HNF1A gene targets in pancreatic beta cells and liver cells. By figuring out key genes regulated by these two transcription components in a tissue-specific method, we make clear their roles in regular tissue perform and the way their dysfunction might contribute to diabetes,” mentioned Dr. Natasha Ng, Senior Scientist at IMCB and the research’s first writer.
The staff subsequent goals to increase this molecular mapping strategy to different diabetes-associated transcriptional regulators and mine the wealthy dataset to uncover extra insights into disease-related mechanisms. Additionally they plan to make the most of genome modifying instruments to appropriate patient-specific variants in HNF4A and HNF1A to straight probe their results in human stem cell-derived fashions.
