Transcriptional genomics associates FOX transcription factors with human heart failure

Sridhar Hannenhalli, Mary E. Putt, Joan M. Gilmore, Junwen Wang, Michael S. Parmacek, Jonathan A. Epstein, Edward E. Morrisey, Kenneth B. Margulies, Thomas P. Cappola

Research output: Contribution to journalArticle

128 Scopus citations

Abstract

BACKGROUND - Specific transcription factors (TFs) modulate cardiac gene expression in murine models of heart failure, but their relevance in human subjects remains untested. We developed and applied a computational approach called transcriptional genomics to test the hypothesis that a discrete set of cardiac TFs is associated with human heart failure. METHODS AND RESULTS - RNA isolates from failing (n=196) and nonfailing (n=16) human hearts were hybridized with Affymetrix HU133A arrays, and differentially expressed heart failure genes were determined. TF binding sites overrepresented in the -5-kb promoter sequences of these heart failure genes were then determined with the use of public genome sequence databases. Binding sites for TFs identified in murine heart failure models (MEF2, NKX, NF-AT, and GATA) were significantly overrepresented in promoters of human heart failure genes (P<0.002; false discovery rate 2% to 4%). In addition, binding sites for FOX TFs showed substantial overrepresentation in both advanced human and early murine heart failure (P<0.002 and false discovery rate <4% for each). A role for FOX TFs was supported further by expression of FOXC1, C2, P1, P4, and O1A in failing human cardiac myocytes at levels similar to established hypertrophic TFs and by abundant FOXP1 protein in failing human cardiac myocyte nuclei. CONCLUSIONS - Our results provide the first evidence that specific TFs identified in murine models (MEF2, NKX, NFAT, and GATA) are associated with human heart failure. Moreover, these data implicate specific members of the FOX family of TFs (FOXC1, C2, P1, P4, and O1A) not previously suggested in heart failure pathogenesis. These findings provide a crucial link between animal models and human disease and suggest a specific role for FOX signaling in modulating the hypertrophic response of the heart to stress in humans.

Original languageEnglish (US)
Pages (from-to)1269-1276
Number of pages8
JournalCirculation
Volume114
Issue number12
DOIs
StatePublished - Sep 2006

Keywords

  • Genomics
  • Heart failure
  • Hypertrophy
  • Remodeling
  • Transcription factors

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Hannenhalli, S., Putt, M. E., Gilmore, J. M., Wang, J., Parmacek, M. S., Epstein, J. A., Morrisey, E. E., Margulies, K. B., & Cappola, T. P. (2006). Transcriptional genomics associates FOX transcription factors with human heart failure. Circulation, 114(12), 1269-1276. https://doi.org/10.1161/CIRCULATIONAHA.106.632430