Characterization of regulatory features of housekeeping and tissue-specific regulators within tissue regulatory networks

Pengping Li,Jin Wang,Zhen Zhang,Jie Li,Xu Hua

doi:10.1186/1752-0509-7-112

Abstract

BackgroundTranscription factors (TFs) and miRNAs are essential for the regulation of gene expression; however, the global view of human gene regulatory networks remains poorly understood. For example, how is the expression of so many genes regulated by limited cohorts of regulators and how are genes differentially expressed in different tissues despite the genetic code being the same in all tissues?ResultsWe analyzed the network properties of housekeeping and tissue-specific genes in gene regulatory networks from seven human tissues. Our results show that different classes of genes behave quite differently in these networks. Tissue-specific miRNAs show a higher average target number compared with non-tissue specific miRNAs, which indicates that tissue-specific miRNAs tend to regulate different sets of targets. Tissue-specific TFs exhibit higher in-degree, out-degree, cluster coefficient and betweenness values, indicating that they occupy central positions in the regulatory network and that they transfer genetic information from upstream genes to downstream genes more quickly than other TFs. Housekeeping TFs tend to have higher cluster coefficients compared with other genes that are neither housekeeping nor tissue specific, indicating that housekeeping TFs tend to regulate their targets synergistically. Several topological properties of disease-associated miRNAs and genes were found to be significantly different from those of non-disease-associated miRNAs and genes.ConclusionsTissue-specific miRNAs, TFs and disease genes have particular topological properties within the transcriptional regulatory networks of the seven human tissues examined. The tendency of tissue-specific miRNAs to regulate different sets of genes shows that a particular tissue-specific miRNA and its target gene set may form a regulatory module to execute particular functions in the process of tissue differentiation. The regulatory patterns of tissue-specific TFs reflect their vital role in regulatory networks and their importance to biological functions in their respective tissues. The topological differences between disease and non-disease genes may aid the discovery of new disease genes or drug targets. Determining the network properties of these regulatory factors will help define the basic principles of human gene regulation and the molecular mechanisms of disease.

Highlights

Transcription factors (TFs) and miRNAs are essential for the regulation of gene expression; the global view of human gene regulatory networks remains poorly understood
A central goal of our study was to classify how regulators are organized to realize gene expression patterns in different cell types and tissues. We have addressed this problem by constructing miRNA-TF regulatory networks for seven human tissues, including brain, heart, kidney, liver, ovary, spleen and testis
Topological bias of TS/HK genes relative to trivial genes Table 1 presents the global view of topological differences among HK and TS genes in the seven tissue regulatory networks relative to randomly selected trivial genes from the same network, i.e. non-HK and non-TS genes

Summary

Introduction

Transcription factors (TFs) and miRNAs are essential for the regulation of gene expression; the global view of human gene regulatory networks remains poorly understood. Different types of genes have different topological properties in human biological networks [8,9,10,11], and these properties can help to identify the functions of new genes. Genes with certain topological properties were found to have particular importance in the organization of human biological networks. The mechanism by which HK and TS encoded regulators (TFs and miRNAs) are organized in gene human regulatory networks and the biological significance of the network properties await elucidation

Methods

Results

Discussion

Conclusion