Abstract
BackgroundRetinal function is ordered by interactions between transcriptional and posttranscriptional regulators at the molecular level. These regulators include transcription factors (TFs) and posttranscriptional factors such as microRNAs (miRs). Some studies propose that miRs predominantly target the TFs rather than other types of protein coding genes and such studies suggest a possible interconnection of these two regulators in co-regulatory networks.ResultsOur lab has generated mRNA and miRNA microarray expression data to investigate time-dependent changes in gene expression, following induction of ischemia-reperfusion (IR) injury in the rat retina. Data from different reperfusion time points following retinal IR-injury were analyzed. Paired expression data for miRNA-target gene (TG), TF-TG, miRNA-TF were used to identify regulatory loop motifs whose expressions were altered by the IR injury paradigm. These loops were subsequently integrated into larger regulatory networks and biological functions were assayed. Systematic analyses of the networks have provided new insights into retinal gene regulation in the early and late periods of IR. We found both overlapping and unique patterns of molecular expression at the two time points. These patterns can be defined by their characteristic molecular motifs as well as their associated biological processes. We highlighted the regulatory elements of miRs and TFs associated with biological processes in the early and late phases of ischemia-reperfusion injury.ConclusionsThe etiology of retinal ischemia-reperfusion injury is orchestrated by complex and still not well understood gene networks. This work represents the first large network analysis to integrate miRNA and mRNA expression profiles in context of retinal ischemia. It is likely that an appreciation of such regulatory networks will have prognostic potential. In addition, the computational framework described in this study can be used to construct miRNA-TF interactive systems networks for various diseases/disorders of the retina and other tissues.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-015-0201-4) contains supplementary material, which is available to authorized users.
Highlights
Retinal function is ordered by interactions between transcriptional and posttranscriptional regulators at the molecular level
Retinal ischemia is a consequence of restrained blood flow that causes severe imbalance between the supply and the demand of nutrients and oxygen resulting in neuronal damage and impaired retinal function [1]
Cell death sub-networks at 24 h vs. 7d post IR-injury We further looked at the regulation of retinal cell death at the two time points, 24 h and 7d, following IR-injury to see if the regulatory loop motifs are the same or not
Summary
Retinal function is ordered by interactions between transcriptional and posttranscriptional regulators at the molecular level. These regulators include transcription factors (TFs) and posttranscriptional factors such as microRNAs (miRs). Retinal ischemia is a consequence of restrained blood flow that causes severe imbalance between the supply and the demand of nutrients and oxygen resulting in neuronal damage and impaired retinal function [1]. Detailed understanding of the molecular events following ischemia-reperfusion induced retinal damage would facilitate development of relevant treatments. The transcriptional regulation of genes is mediated in part by transcription factors (TFs), while their post-transcriptional regulation is mediated in part by small non coding RNAs, a prominent class of which are microRNAs (miRs) [13]. Despite the different levels of regulation, both transcriptional and post-transcriptional regulatory interactions are not isolated from each other, but interact to execute complex regulatory programs which, in turn, modulate cellular
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