SRA

Insufficient insulin release by ß-cells is the primary etiology in type 2 diabetes (T2D) and coincides with impaired expression of genes essential to ß-cell function, but drivers of gene expression dysregulation are not well resolved. We find that H3K4me3 peak breadth correlates with gene expression dysregulation in T2D. Using an adult ß-cell Dpy30-KO mouse model, we show that global reduction of H3K4 methylation causes downregulation of genes also downregulated in T2D. Reduction of H3K4 methylation increases transcriptional entropy and reduces insulin production and glucose-responsiveness. Depletion of H3K4 methylation causes global dilution of epigenetic complexity but does not generally reduce gene expression – instead, genes related to ß-cell function and/or in particular chromatin environments are specifically affected. Our data further suggests that promoter-associated H3K4me1 is sufficient to maintain expression in the absence of H3K4me3. These data implicate dysregulation of H3K4 methylation in destabilizing gene expression and contributing to ß-cell dysfunction in T2D. Overall design: RNA-seq of 3 replicates at 2 time points, scRNA-seq of 1 replicate at 1 time point, from Dpy30-KO or CTRL mouse beta cells Please note that the "scRNAseq_commands.txt" contains the processing pipeline details to regenerate the processed data from raw data for scRNA-seq. The file "mtmg_long.fa" containing egfp and tdtomato sequences is necessary to regenerate the processed data.