Elevated H3K4me1 in pancreatic acinar cells mediates stress granule formation in response to hyperglycemia in diabetes

Diabetes mellitus (DM) promotes a stressed state in pancreatic cells, particularly pancreatic acinar cells. However, the alterations in stress granules (SGs) under this pathological condition and the mechanisms underlying these changes remain unclear. Single-cell RNA sequencing data from human pancreatic tissues in the context of DM were first analyzed to explore cellular alterations. Acinar cells were then subtyped based on the expression of SG-related genes. Chromatin immunoprecipitation sequencing (ChIP-seq) data for H3K4me1 were further integrated to investigate the relationship between H3K4me1 and SG alterations in acinar cells. Finally, in vitro experiments, including Western blotting, immunofluorescence, and ChIP-qPCR were performed to validate diabetes-associated changes in SGs and the role of H3K4me1 in these processes. Under DM conditions, the proportion of pancreatic acinar cells decreased, whereas the proportion of SG-positive (SG⁺) cells increased. In vitro experiments demonstrated that a high-glucose (HG) environment promoted the phosphorylation of eIF2α, the expression of G3BP1 and TIA1, and enhanced SGs aggregation. The H3K4me1 modification level was elevated in diabetes, which drove SGs formation. Inhibition of H3K4me1 reduced G3BP1 and TIA1 expression and decreased stress granule formation. DM or a HG environment reduces the proportion of pancreatic acinar cells while promoting their stressed state and SG formation. Upregulation of H3K4me1 represents an epigenetic mechanism underlying this phenomenon.