Dynamic gene expression patterns in animal models of early and late heart failure reveal biphasic-bidirectional transcriptional activation of signaling pathways

Janelle Rowell, Norimichi Koitabashi, David A. Kass, Andreas S. Barth

Research output: Contribution to journalArticle

Abstract

Altered cardiac gene expression in heart failure (HF) has mostly been identified by single-point analysis of end-stage disease. This may miss earlier changes in gene expression that are transient and/or direction-ally opposite to those observed later. Myocardial datasets from the largest microarray data repository (Gene Expression Omnibus) yielded six HF studies with time-course data. Differentially expressed transcripts between nonfailing controls, early HF (<3 days after cardiac insult) and late HF (usually >2 wk) were determined, and analysis of KEGG pathways and predicted regulatory control elements performed. We found that gene expression followed varying patterns: Downregulation of metabolic pathways occurred early and was sustained into late-stage HF. In contrast, most signaling pathways undergo a complex biphasic pattern: Calcium signaling, p53, apopto-sis, and MAPK pathways displayed a bidirectional response, declining early but rising late. These profiles were compatible with specific microRNA (miRNA) and transcription regulators: Estrogen-related receptor-a and myocyte-enhancer factor-2 binding sites were over-represented in the promoter regions of downregulated transcripts. Concurrently, there were overrepresented binding sites for E2f and ETS family members (E-Twenty Six, including Gabp, Elf1, and Ets2), serum response and interferon regulated factor in biphasic-bidirectional and late-upregulated transcripts. Binding sites for miRNAs downregulated by HF were more common in upregulated transcripts (e.g., miRNA-22,-133a/b, and -150 in early HF and miRNA-1,-9,-499 in late HF). During the development of HF, gene expression is characterized by dynamic overlapping sets of transcripts controlled by specific interrelated regulatory mechanisms. While metabolic gene classes show early and sustained downregulation in HF, signaling pathways undergo a complex biphasic pattern with early down- and more pronounced late upregulation.

Original languageEnglish (US)
Pages (from-to)779-787
Number of pages9
JournalPhysiological Genomics
Volume46
Issue number20
DOIs
StatePublished - Oct 15 2014

Keywords

  • Gene expression
  • Genomics
  • Heart failure
  • Meta-analysis
  • Signaling pathways

ASJC Scopus subject areas

  • Physiology
  • Genetics

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