Type-II diabetes is a chronic disease caused by insulin resistance due to pancreatic β-cell dysfunction. Mutations in a single gene, HNF1A, which codes for the transcription factor hepatocyte nuclear factor-1 alpha, are known to cause MODY3, a rare, early onset form of diabetes that affects around 0.03% of the general population. Smaller scale mutations in the same gene can lead to type-II diabetes, which impacts more than one in nine adults or around 600 million people worldwide. Scientists have now attributed the molecular mechanism by which these HNF1A mutations lead to disease to dysregulated RNA splicing.
In a new study published in Cell Metabolism titled, “HNF1A and A1CF coordinate a beta cell transcription-splicing axis that is disrupted in type II diabetes,” researchers from the Centre for Genomic Regulation (CRG) in Barcelona found that deleting HNF1A in either human or mouse β‑cells impacted the expression of more than one hundred genes, many of which encode for the molecular parts required to transport and release insulin. This faulty genomic regulation presents a new druggable path against early onset forms of diabetes.
To systematically examine the cell types in which HNF1A is essential for regulating glucose levels, the authors deleted HNF1A in cells found in the liver, gut and both α and β‑cells in the pancreas. Blood glucose levels were only affected when the gene was deleted in β‑cells. Notably, the team found that one of the direct targets of HNF1A was A1CF, a gene involved in RNA editing and alternative splicing. Mutation in HNF1A massively dysregulated RNA splicing in β‑cells, leading to impaired insulin secretion.
“When HNF1A fails, two things go wrong at once. Hundreds of genes that depend on it begin to work incorrectly. That alone is enough to weaken insulin secretion, but the loss of A1CF means that the RNAs that are still made now get spliced incorrectly. Both layers matter, but the first hit is broader and sets the stage while the second piles on extra dysfunction,” said Matías Gonzalo De Vas, researcher at Imperial College London and co-first author of the study.
When analyzing human pancreatic cells from donors with type-II diabetes, researchers observed a major increase in populations of cells with low HNF1A and A1CF activity in contrast to healthy pancreatic cells.
“In people with type-II diabetes, for every high-functioning β‑cell we found about eight low-functioning ones, while healthy donors had a healthier ratio of one to one. It’s a dramatic shift that shows how a single mutation can cascade into the loss of function of entire tissues and organs,” said Edgar Bernardo, PhD, postdoctoral researcher at CRG and co-first author of the study.
Jorge Ferrer, PhD, group leader at CRG and corresponding author of the study explains that existing therapies for diabetes try to lower blood sugar with different strategies without correcting underlying defects. “The RNA defects we found are patchable, offering a rare, clear target for an incredibly complex disease,” said Ferrer.
At the same time, type-II diabetes is driven by many genes and lifestyle factors. “We can now say this defective program has a causal contribution, but there are other molecular defects that also need to be addressed. This is only one piece of a larger puzzle that we’ll also have to solve,” Ferrer continued.
Looking ahead, the research group plans to identify practical targets for new β‑cell therapies within this genetic mechanism to provide more treatment options for diabetes.
The post RNA Splicing Mechanism Opens Path to Treat Diabetes appeared first on GEN – Genetic Engineering and Biotechnology News.
