Aberration of the modulatory functions of intronic microRNA hsa-miR-933 on its host gene ATF2 results in type II diabetes mellitus and neurodegenerative disease development

Abstract

Background: MicroRNAs are ~ 22-nucleotide-long biological modifiers that act as the post-transcriptional modulator of gene expression. Some of them are identified to be embedded within the introns of protein-coding genes, these miRNAs are called the intronic miRNAs. Previous findings state that these intronic miRNAs are co-expressed with their host genes. This co-expression is necessary to maintain the robustness of the biological system. Till to date, only a few experiments are performed discretely to elucidate the functional relationship between few co-expressed intronic miRNAs and their associated host genes.

Results: In this study, we have interpreted the underlying modulatory mechanisms of intronic miRNA hsa-miR-933 on its target host gene ATF2 and found that aberration can lead to several disease conditions. A protein-protein interaction network-based approach was adopted, and functional enrichment analysis was performed to elucidate the significantly over-represented biological functions and pathways of the common targets. Our approach delineated that hsa-miR-933 might control the hyperglycemic condition and hyperinsulinism by regulating ATF2 target genes MAP4K4, PRKCE, PEA15, BDNF, PRKACB, and GNAS which can otherwise lead to the development of type II diabetes mellitus. Moreover, we showed that hsa-miR-933 can regulate a target of ATF2, brain-derived neurotrophic factor (BDNF), to modulate the optimal expression of ATF2 in neuron cells to render neuroprotection for the inhibition of neurodegenerative diseases.

Conclusions: Our in silico model provides interesting resources for experimentations in a model organism or cell line for further validation. These findings may extend the common perception of gene expression analysis with new regulatory functionality.

Keywords: ATF2; Intronic microRNA; MicroRNA; Neurodegenerative diseases; diabetes mellitus; hsa-miR-933.

Fig. 1

a UCSC Genome Browser view of ATF2 and miR-933. miR-933 expression in b different tissue types and c different bodily fluids. d ATF2 expression in different tissue type. e Common target genes of ATF2 and hsa-miR-933. f The PPI network shows an existing connection between PRKCE, PRKACB, and GNAS

Fig. 2

Enrichment of hsa-miR-933 and ATF2 target genes showing an over-representation of the terms related to type II diabetes mellitus. a Enrichment GOBP (GO biological process). b Enrichment of KEGG pathways. c Genes that are significantly over-represented in both categories for glucose homeostasis disruption. Selected significant terms are represented in the color-coded heatmap. The significance of enrichment in terms of the adjusted p value (< 0.05) is represented in the p value scale for all heatmaps. Color towards red indicates higher significance, and color towards yellow indicates less significance, while gray means non-significant

Fig. 3

Putative regulatory network for the development of type II diabetes mellitus by target genes of ATF2 and hsa-miR-933. Modes of action are shown in different colors

Fig. 4

Schematic representation of the a projected mechanism for the development of type II diabetes mellitus mediated by hyperinsulinemia and hyperglycemia by ATF2 target genes GNAS, MAP4K4, PRKACB, PRKCE, PEA15, and BDNF. b Putative regulatory circuitry for controlling type II diabetes mellitus by regulating ATF2 target genes MAP4K4, PRKCE, PEA15, BDNF, PRKACB, and GNAS by hsa-miR-933

Fig. 5

Enrichment of hsa-miR-933 and ATF2 targets showing an over-representation of neuronal degeneration. a Enrichment GOBP (GO biological process). b Enrichment of KEGG pathways. c Genes that are significantly over-represented in both categories. Selected significant terms are represented in the color-coded heatmap. The significance of enrichment in terms of the adjusted p value (< 0.05) is represented in the p value scale for all heatmaps. Color towards red indicates higher significance, and color towards yellow indicates less significance, while gray means non-significant

Fig. 6

Putative regulatory network for neurodegenerative disease by ATF2 and miR-933 target genes. Modes of action are shown in different colors

Fig. 7

Putative controlling model of neurodegeneration by regulating ATF2 target genes PRKCE and BDNF by miR-933