Candidate master microRNA regulator of arsenic-induced pancreatic beta cell impairment revealed by multi-omics analysis

ABSTRACT: Arsenic is a pervasive environmental toxin that is ranked as the number one investigative priority by the Agency for Toxic Substance and Disease Registry. Chronic exposure to arsenic has been associated with type 2 diabetes (T2D). However, the underlying mechanisms remain largely unknown. We have recently demonstrated that arsenic treatment of INS-1 832/13 pancreatic beta-cells impairs glucose stimulated insulin secretion (GSIS), a hallmark of T2D. We have also shown that arsenic alters the microRNA (miRNA) profile in beta-cells more dramatically than other metals. miRNAs have a well-established regulatory role in both normal beta-cell function and T2D pathogenesis. We hypothesized that there are miRNA master regulators that mediate arsenic-associated GSIS defects. To test this hypothesis, we first treated INS-1 832/13 beta-cells with either 1 μM of inorganic arsenic (iAsIII) or 0.5 μM of monomethylarsenite (MAsIII) and confirmed that GSIS is significantly reduced. We then performed multi-omic analysis using chromatin run-on sequencing (ChRO-seq), RNA-sequencing (RNA-seq), and small RNA-seq in order to define arsenic-associated chromatin and transcriptional activity, gene expression, and miRNA profiles, respectively. Integrating across these data sets we first showed that genes downregulated by iAsIII treatment are enriched in insulin secretion, T2D, and maturity onset diabetes of the young (MODY) pathways, whereas genes downregulated by MAsIII treatment are enriched in cell cycle and include genes that encode the critical beta cell maintenance factors Neurod1 and Rfx6. Secondly, we also identified those genes that are subject primarily to post-transcriptional regulation in response to arsenicals. Finally, we demonstrated that miR-29a is the top candidate master regulator of these genes. Our study is the first multi-omic analysis of beta cells after exposure to arsenicals, and the results strongly suggest that arsenicals lead to aberrant miR-29 expression and activity in beta-cells, which in turn leads to the repression of critical genes for beta-cell function, ultimately predisposing to diabetes.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE199458 | GEO | 2026/03/01

REPOSITORIES: GEO