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 listed as the top priority for investigation by the Agency for Toxic Substance and Disease Registry. While chronic exposure to arsenic is associated with type 2 diabetes (T2D), the underlying mechanisms are largely unknown. We have recently demonstrated that arsenic treatment of INS-1 832/13 pancreatic beta cells impairs glucose-stimulated insulin secretion (GSIS), a T2D hallmark. We have also shown that arsenic alters the microRNA profile of beta cells. MicroRNAs have a well-established post-transcriptional regulatory role in both normal beta cell function and T2D pathogenesis. We hypothesized that there are microRNA master regulators that shape beta cell gene expression in pathways pertinent to GSIS after exposure to arsenicals. To test this hypothesis, we first treated INS-1 832/13 beta cells with either inorganic arsenic (iAsIII) or monomethylarsenite (MAsIII) and confirmed GSIS impairment. We then performed multi-omic analysis using chromatin run-on sequencing, RNA-sequencing, and small RNA-sequencing to define profiles of transcription, gene expression, and microRNAs, respectively. Integrating across these data sets, we first showed that genes downregulated by iAsIII treatment are enriched in insulin secretion and T2D pathways, whereas genes downregulated by MAsIII treatment are enriched in cell cycle and critical beta cell maintenance factors. We also defined the genes that are subject primarily to post-transcriptional control in response to arsenicals and demonstrated that miR-29a is the top candidate master regulator of these genes. Our results highlight the importance of microRNAs in arsenical-induced beta cell dysfunction and reveal both shared and unique mechanisms between iAsIII and MAsIII.

The Role of microRNAs in Arsenic-Induced Human Diseases: A Review

“…Arsenic is classified as a human carcinogen, which can lead to many adverse health effects including DM, − skin lesions, , kidney disease, , neurological impairment, , cancer, , male reproductive injury, and CVD. , miRNAs dysregulation was considered to be one of the important mechanisms by which arsenic leads to toxicity and human diseases. ,,,, miRNAs can act as tumor suppressors and oncogenes, and the balance between the above two roles determined its carcinogenic potential. The following miRNAs were downregulated by arsenic, including miR-217, miR-182-5p, miR-455, Let-7a/b/c, miR-181b, miR-9, miR-200b/c, miR-410, miR-548ac, miR-3174, miR-138, miR-205, miR-34c-5p, miR-143, miR-181d/c, miR-6733, miR-148a, miR-373, and miR-134, while the majority of miRNAs that function as oncogenes are upregulated by arsenic exposure, such as miR-638, miR-155, miR-21, miR-889, miR-15b, miR-191, miR-186, miR-200a, miR-141, miR-190, miR-330-5p, miR-6734-5p, miR-885-5p, miR-184, miR-576-3p, miR-222, miR-221, and miR-451, which can directly target and inhibit the expression of tumor suppressors of RNF4, TGFβ1, VEGF, PDCD4, PTEN, Spry1, DAB2IP, LATS1, BASP1, BUB1, ACVR2A, CDK6, BMPR2, PHLPP, Skp2, IDH2, and MTPN.…”

“…After treating INS-1 832/13 pancreatic beta cells with iAs III , the genes associated with the insulin secretion pathway, beta cell function maintenance and cell cycle were down-regulated by MAs III . Moreover, miR-29a was considered a master regulator of these genes . Glucose metabolism disorder defined as decreased hepatic glycogen levels and glucose transporter 4 (GLUT4) was found in mice after chronic exposure to arsenic in drinking water for 12 months .…”

“…A recent study highlighted the critical role of miRNAs in beta cell dysfunction induced by arsenic, which suggested that miR-29a was involved in the DM caused by iAs III or MAs III via impairing glucose-stimulated insulin secretion (GSIS). 33 After treating INS-1 832/13 pancreatic beta cells with iAs III , the genes associated with the insulin secretion pathway, beta cell function maintenance and cell cycle were down-regulated by MAs III . Moreover, miR-29a was considered a master regulator of these genes.…”

“…Moreover, miR-29a was considered a master regulator of these genes. 33 Glucose metabolism disorder defined as decreased hepatic glycogen levels and glucose transporter 4 (GLUT4) was found in mice after chronic exposure to arsenic in drinking water for 12 months. 191 Up-regulated miR-191, and decreased phospho-protein kinase B (p-AKT), insulin receptor substrate 1 (IRS1), and p-IRS1 were also observed in L-02 cells and the liver of mice.…”

“…More than 50 million people from West Bengal and Bangladesh were exposed to arsenic levels above 50 μg/L, which caused frequent arsenic poisoning and adverse effects on human health . A growing body of literature suggests that arsenic disrupts a series of cellular processes, including oxidative stress, cell proliferation, inflammation, and autophagy and apoptosis. ,− Arsenic exposure can lead to many adverse health effects of diabetes mellitus (DM), − skin lesions, , kidney disease, , neurological impairment, , cancers, , male reproductive injury, and cardiovascular disease (CVD) as cardiac arrhythmias, endothelial dysfunction, and ischemic heart failure. , …”