Background
Heart failure is a rapidly growing public health issue and one of leading cause of death [
1]. Serial vicious cycles of cardiomyocyte depletion, cardiac dilatation and mechanical dysfunction are culminating in heart failure [
2]. Once patients have developed to the end stage of heart failure, intervention is limited to heart transplantation [
3]. In order to understand the molecular mechanisms regulating heart failure, several studies have used microarrays for genome wide analysis of heart failure [
4‐
6]. Transcriptional genomics results revealed that FOX families of transcription factors were associated with human heart failure [
4]. The different mRNA splicing [
5] and long non-coding RNA (lncRNA) [
6] in diseased hearts was also comprehensively studied using gene microarrays. However, due to the complexity of genetic and epigenetic abnormality of heart failure, the previously reported gene expression signature in failing heart tissues is varied considerably from study to study, making it difficult to reconcile their findings or reach any definite conclusions [
7]. Moreover, the mis-regulated molecular signaling pathways and key transcription factors in heart failure are largely unknown.
Transcription factors control the transcriptional activity of multiple target genes by binding to a specific region of the DNA sequence [
8]. It has been reported that transcription factor C/EBPβ plays central roles in physiologic hypertrophy and heart failure [
9]. C/EBPβ could repress cardiomyocyte growth and proliferation. Reducing C/EBPβ expression exaggerates the cardiac failure upon pressure overload [
9]. TP53 is another major transcription factor in cardiac transcriptional network [
10]. TP53 deficient hearts are resistant to the failure development upon acute pressure overload [
11]. Interestingly, both C/EBPβ and TP53 are involving tumor developmental progress by regulating metabolism [
12,
13] and TGFβ signaling pathway [
14,
15].
MYC is an oncogene. High level of MYC expression is required for tumor initiation, progression and maintenance [
16]. MYC regulates multiple critical cellular functions, for example, metabolism [
17] and RNA splicing [
18]. Inhibition of MYC by BET bromodomain inhibitor is a promising anti-cancer strategy [
19]. Interestingly, transcriptional pause release in heart failure was mediated by BET bromodomain [
20], and BET bromodomain inhibitors could suppresses the development of heart failure by the regulation of the innate inflammatory network [
21]. All those results suggest the potentially significant roles of MYC in heart failure. However, the expression of MYC and MYC mediated downstream target genes are not studied in failing heart patients.
In the present study, using published GEO datasets, we tried to identify the signaling pathways and transcription factors associated with heart failure. We also tried to determine the MYC and C/EBPβ mediated downstream target genes and construct the complex transcriptional networks regulated by MYC and C/EBPβ in heart failure developmental progress.
Discussion
Complex diseases like heart failure are often involving malfunctions of multiple genes. Disease related genes detected by different microarray studies are often highly inconsistent, even when there is not much technical noise [
7]. As described in the present study, compared with normal heart tissues, there are 2184 differentially expressed genes in failing heart tissues in GSE5406, 1644 genes in GSE16499 and 3477 genes in GSE68316 dataset. However, only 90 genes are commonly up/down regulated in all three datasets. Those differentially expressed genes are associated with MYC and C/EBPβ transcription factors, metabolism signaling pathways and insulin signaling pathway. The converged transcription factors or signaling pathways may have particularly significant roles in heart failure development than single gene.
Indeed, C/EBPβ, MYC and their target genes are all down regulated in failing heart tissues. C/EBPβ is a master regulator in the development of heart failure [
9]. Also, some C/EBPβ target genes, for example, OSMR [
34], MAP2K3 [
35] regulate the heart failure developmental progress. The functions of MYC in the regulating of heart failure development are rather complicated. Previous report suggests that inhibition of MYC is a potential therapeutic approach in the treatment of hypertrophic cardiomyopathy [
29]. However, we observe the down regulation of MYC expression in failing heart tissues. MYC target genes are also decreased in failing heart tissues. The inconsistence further emphases the complex transcriptional network regulated by MYC and the complex developmental progress of heart failure.
The aim of the current study is to identify the molecular signaling pathways and transcription factors involving failing heart development. By comparative analysis, our results provide the changed expression profiling of metabolism signaling pathway, insulin signaling pathway, transcription factors MYC and C/EBPβ in the development of heart failure. However, there are certain limitations to the current study. The conclusions were drawn from published databases and lack of further functional validation in failing heart tissues. Therefore, quantitative PCR would have been performed to validate the enriched MYC and C/EBPβ genes in failing heart tissues. Furthermore, the precise mechanisms of MYC and C/EBPβ in heart failure development require further elucidation by MYC and C/EBPβ knockout mouse. Nevertheless, our analysis suggests that transcription factor MYC and C/EBPβ play critical roles in heart failure developmental progress.
Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit
http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (
http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.