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

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.

Role of microRNAs in obesity and obesity-related diseases

“…Moreover, miRNAs have been clustered into families constructed on seed region similarity, which is accountable for the corresponding ability to target common groups of gene transcripts [ 34 ]. Although some miRNAs exhibit a tissue-specific localization, most miRNAs show a broader tissue distribution [ 35 ]. Each miRNA can simultaneously regulate large cohorts of transcripts, and individual mRNA may include multiple binding sites for different miRNAs originating an intricate regulatory network [ 32 , 36 ].…”

Naïve Bayes classifier predicts functional microRNA target interactions in colorectal cancer

“…Although a number of studies have shown that miRNA function is tissue specific (see for example 12,37 ) so far no study has offered an algorithm to predict miRNA targets for a specific disease.…”

Three topological features of regulatory networks control life-essential and specialized subsystems

“…The good performance of the normal consensus model to classify the species-specific test sets indicates that the K nn , page rank, and degree are topological features conserved along the evolution. Notwithstanding, the good classification of GRNs from mouse embryonic stem cells also showed that these topological features arise as essential properties even before the cell differentiation, albeit a previous paper showed that the topological properties of TFs are different amongst tissues 56 , reflecting different cell states 34 .…”