Transcription factors in the associative gene network of the renin-angiotensin-aldosterone system in humans

Background and objectives

Empirical and theoretical studies can be distinguished among the areas of investigation of the renin-angiotensin-aldosterone system (RAAS) and its relationship with the development of cardiovascular diseases. Theoretical work is based mainly on the bioinformatic analysis of key elements of RAAS (genes, proteins, metabolites), on calculations and predictions of protein interactions, and on mechanisms of RAAS gene expression regulation. An associative gene network based on big data analysis allows us to reveal relationships among the proteins, regulatory pathways, and biological processes acting in RAAS, as well as to identify new diagnostic markers, therapeutic targets, putative molecular mechanisms of the development of RAAS-associated diseases, drug interactions, and drug toxicity.

Methods

The reconstruction and analysis of associative gene networks were performed using ANDSystem. The regulation of RAAS-associated gene expression was analyzed by transcription factor (TF) binding sites (TFBSs) prediction in the proximal promoters of these genes and by studying interactions between TFs themselves using the Ensembl Biomart web service and AnimalTFDB 4.0. The recognition of potential TFBSs in RAAS gene promoters was performed using MoLoTool.

Results

According to the centrality criteria of the RAAS associative gene network, the following proteins were identified as exerting a significant influence on information interplay between network components: IL6, EDN1, TNFA, MK01, LEP, and JUN. Analysis of the ten identified TFs and their TFBSs among the genes in the RAAS network under study revealed clusters of three to 26 genes regulated by them.

Conclusions

We reconstructed the associative network of the RAAS genes based on information from publications and databases by using the ANDSystem computer program developed at the Institute of Cytology and Genetics, Novosibirsk. We found that the IL6, EDN1, TNFA, MK01, LEP, and JUN proteins have the highest mediation values, which point to their significance in transmitting information between other network components. We also analyzed TFBSs in the proximal [−300;1] promoters of the RAAS genes and interactions between the TFs themselves in order to understand mechanisms regulating the expression of genes associated with RAAS. Bioinformatics analysis of TFs and their binding sites among the genes in the resulting associative network of RAAS revealed 10 TFs that appear to regulate clusters of genes. This result provides new information on RAAS mechanisms with regard to the coordinated and finely regulated interaction of RAAS components themselves, i.e., genes, their proteins, and their regulators, TFs.

Full text

https://www.xiahepublishing.com/1555-3884/GE-2025-00050

The study was recently published in the Gene Expression.

Gene Expression (GE) is an open-access journal. It was launched in 1991 by Chicago Medical School Press, and transferred to Cognizant Communication Corporation in 1994. From August 2022, GE is published by Xia & He Publishing Inc.   

GE publishes peer-reviewed and high-quality original articles, reviews, editorials, commentaries, and opinions on its primary research topics including cell biology, molecular biology, genes, and genetics, especially on the cellular and molecular mechanisms of human diseases. 

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