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Biological Pathways Leading From ANGPTL8 to Diabetes Mellitus-A Co-expression Network Based Analysis

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Biological Pathways Leading From ANGPTL8 to Diabetes Mellitus-A Co-expression Network Based Analysis

Amnah Siddiqa et al. Front Physiol.

Abstract

Angiopoietin like protein 8 (ANGPTL8) is a newly identified hormone with unique nature due to its ability to regulate both glucose and lipid metabolic pathways. It is characterized as an important molecular player of insulin induced nutrient storage and utilization pathway during fasting to re-feeding metabolic transition. Several studies have contributed to increase our knowledge regarding its function and mechanism of action. Moreover, its altered expression levels have been observed in Insulin Resistance, Diabetes Mellitus (Types I & II) and Non Alcohlic Fatty Liver Disease emphasizing its assessment as a drug target. However, there is still a great deal of information that remains to be investigated including its associated biological processes, partner proteins in these processes, its regulators and its association with metabolic pathogenesis. In the current study, the analysis of a transcriptomic data set was performed for functional assessment of ANGPTL8 in liver. Weighted Gene Co-expression Network Analysis coupled with pathway analysis tools was performed to identify genes that are significantly co-expressed with ANGPTL8 in liver and investigate their presence in biological pathways. Gene ontology term enrichment analysis was performed to select the gene ontology classes that over-represent the hepatic ANGPTL8-co-expressed genes. Moreover, the presence of diabetes linked SNPs within the genes set co-expressed with ANGPTL8 was investigated. The co-expressed genes of ANGPTL8 identified in this study (n = 460) provides narrowed down list of molecular targets which are either co-regulated with it and/or might be regulation partners at different levels of interaction. These results are coherent with previously demonstrated roles and regulators of ANGPTL8. Specifically, thirteen co-expressed genes (MAPK8, CYP3A4, PIK3R2, PIK3R4,PRKAB2, G6PC, MAP3K11, FLOT1, PIK3C2G, SHC1, SLC16A2, and RAPGEF1) are also present in the literature curated pathway of ANGPTL8 (WP3915). Moreover, the gene-SNP analysis of highly associated biological processes with ANGPTL8 revealed significant genetic signals associated to Diabetes Mellitus and similar phenotypic traits. It provides meaningful insights on the influencing genes involved and co-expressed in these pathways. Findings of this study have implications in functional characterization of ANGPTL8 with emphasis on the identified genes and pathways and their possible involvement in the pathogenesis of Diabetes Mellitus and Insulin Resistance.

Keywords: ANGPTL8; Co-expression network analysis; diabetes mellitus; transcriptomics data analysis; wikiPathways.

Figures

Figure 1
Figure 1
Integrated workflow deployed for functional assessment of ANGPTL8: The steps and the tools/softwares used for the the quality control assessment, construction of ANGPTL8 co-expression network, Gene Ontology analysis, pathway analysis and variant effect prediction analysis (through SNPs identification) are described.
Figure 2
Figure 2
The dendrogram of dissimilarity TOM Matrix constructed using hierarchical clustering. Each vertical line corresponds to the gene. Module colors are provided at the bottom. Each color corresponds to the separate genes module.
Figure 3
Figure 3
Gene-pathway network with information of genes and variants associated to DM and other metabolic disorders. The top ten pathways identified with maximum number of genes in WikiPathways human curated collection are illustrated as green diamonds. The pathways are connected with seventy two genes (circles and triangles) and the size of the gene nodes indicate that the gene is either a hub gene (large nodes) or not (small nodes) in the co-expression network of ANGPTL8. The dark blue nodes indicate genes associated with DM. The aqua color nodes are the genes associated with GSD1. The triangle shapes represent the genes with a SNPs associated to DM or other metabolic disorders. ANGPTL8 gene is highlighted in red.
Figure 4
Figure 4
Presence of co-expressed genes of ANGPTL8 in the ANGPTL8 Regulatory Pathway (pathway id:WP3915 (www.wikipathways.org/instance/WP3915)). Thirteen genes in the ANGPTL8 regulatory pathway which are also identified to be co-expressed with it are marked with red color. These genes (MAPK8, CYP3A4, PIK3R2, PIK3R4, PRKAB2, ANGPTL8, G6PC, MAP3K11, FLOT1, PIK3C2G, SHC1, SLC16A2, RAPGEF1) belong to different signaling arms of the pathway. Among these genes, SHC1 and PIK3C2G are also identified as hub genes.

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