Transcriptomic analysis of neuregulin-1 regulated genes following ischemic stroke by computational identification of promoter binding sites: A role for the ETS-1 transcription factor.

Monique C Surles-Zeigler,Hakeem Omotayo,Yonggang Li,Byron D Ford,Timothy J Distel,Shaokui Ge,Honglian Shi

doi:10.1371/journal.pone.0197092

Monique C Surles-Zeigler, Hakeem Omotayo + Show 5 more

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https://doi.org/10.1371/journal.pone.0197092

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Abstract

Ischemic stroke is a major cause of mortality in the United States. We previously showed that neuregulin-1 (NRG1) was neuroprotective in rat models of ischemic stroke. We used gene expression profiling to understand the early cellular and molecular mechanisms of NRG1’s effects after the induction of ischemia. Ischemic stroke was induced by middle cerebral artery occlusion (MCAO). Rats were allocated to 3 groups: (1) control, (2) MCAO and (3) MCAO + NRG1. Cortical brain tissues were collected three hours following MCAO and NRG1 treatment and subjected to microarray analysis. Data and statistical analyses were performed using R/Bioconductor platform alongside Genesis, Ingenuity Pathway Analysis and Enrichr software packages. There were 2693 genes differentially regulated following ischemia and NRG1 treatment. These genes were organized by expression patterns into clusters using a K-means clustering algorithm. We further analyzed genes in clusters where ischemia altered gene expression, which was reversed by NRG1 (clusters 4 and 10). NRG1, IRS1, OPA3, and POU6F1 were central linking (node) genes in cluster 4. Conserved Transcription Factor Binding Site Finder (CONFAC) identified ETS-1 as a potential transcriptional regulator of NRG1 suppressed genes following ischemia. A transcription factor activity array showed that ETS-1 activity was increased 2-fold, 3 hours following ischemia and this activity was attenuated by NRG1. These findings reveal key early transcriptional mechanisms associated with neuroprotection by NRG1 in the ischemic penumbra.

Highlights

Stroke is the 5th leading cause of death in the United States, with ischemic stroke being most prevalent [1, 2]
To capture the mechanisms involved in the initial stages of neuronal injury that occurs in the penumbra, we identified gene expression profiles altered following NRG1 treatment at 3 hours following ischemic stroke and the transcription factors that regulated the expression of these genes
Using MRI, we showed that the neuroprotective effects were seen as early as 1 hour following ischemia in subcortical brain regions [33]

Summary

Introduction

Stroke is the 5th leading cause of death in the United States, with ischemic stroke being most prevalent [1, 2]. The molecular events initiated by ischemic stroke activate several biological cascades, leading to cell death. Tissue plasminogen activator (tPA) is the only. Regulation of ETS-1 in stroke by neuregulin preparation of the manuscript. There was no additional external funding received for this study

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