Large-Scale Analysis of Drug Side Effects via Complex Regulatory Modules Composed of microRNAs, Transcription Factors and Gene Sets

Xiaodong Jia,Yunfeng Wang,Xiusen Bian,Mingliang Gu,Xiangqiong Liu,Hongzhe Ma,Qing Jin,Lei Liu,Xiujie Chen,Fujian Tan

doi:10.1038/s41598-017-06083-5

Abstract

Identifying the occurrence mechanism of drug-induced side effects (SEs) is critical for design of drug target and new drug development. The expression of genes in biological processes is regulated by transcription factors(TFs) and/or microRNAs. Most of previous studies were focused on a single level of gene or gene sets, while studies about regulatory relationships of TFs, miRNAs and biological processes are very rare. Discovering the complex regulating relations among TFs, gene sets and miRNAs will be helpful for researchers to get a more comprehensive understanding about the mechanism of side reaction. In this study, a framework was proposed to construct the relationship network of gene sets, miRNAs and TFs involved in side effects. Through the construction of this network, the potential complex regulatory relationship in the occurrence process of the side effects was reproduced. The SE-gene set network was employed to characterize the significant regulatory SE-gene set interaction and molecular basis of accompanied side effects. A total of 117 side effects complex modules including four types of regulating patterns were obtained from the SE-gene sets-miRNA/TF complex regulatory network. In addition, two cases were used to validate the complex regulatory modules which could more comprehensively interpret occurrence mechanism of side effects.

Highlights

Biological processes are regulated by its target miRNAs and TFs
Four regulatory patterns were identified, and the possible occurrence mechanism of side effects regulated by multiple patterns of complex regulatory modules was analyzed from an overall perspective for every side effect
We found that blurred vision was highly related with the gene sets of endosome transport, which coincides with the norepinephrine releasing, transporting and binding to the beta-2 sympathetic receptors of the ciliary muscle, these biological processes are mediated by endosome signal transduction[8]

Summary

Introduction

Biological processes are regulated by its target miRNAs and TFs. The composite regulatory modules are composed of TFs, miRNA and biological processes. miRNAs, TFs and their target mRNAs (genes) can interact with each other, and form a complex regulated system to the biological processes inducing side effects. MiRNAs, TFs and their target mRNAs (genes) can interact with each other, and form a complex regulated system to the biological processes inducing side effects. Studying the molecular mechanism of side effects only from the aspect of genes/gene sets is far from enough, and discovering the mechanism from the interaction among TFs, miRNAs and biological processes will be more comprehensive. To our knowledge, this is the first article to study the relationship among miRNAs, TFs and biological processes in side effects. This study used multiple bioinformatics methods to interpret the mechanism of side effects from a new perspective, and contributed the guidelines to the drug development and clinical application

Methods

Results

Conclusion