Published Online
on September 4, 2006

A more recent version of this article appeared on September 19, 2006

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Submitted on April 9, 2006
Revised on July 18, 2006
Accepted on July 25, 2006

Transcriptional Genomics Associates FOX Transcription Factors With Human Heart Failure

Sridhar Hannenhalli PhD, Mary E. Putt PhD, ScD, Joan M. Gilmore BS, Junwen Wang PhD, Michael S. Parmacek MD, Jonathan A. Epstein MD, Edward E. Morrisey PhD, Kenneth B. Margulies MD, and Thomas P. Cappola MD, ScM^*

From the Department of Genetics and Penn Center for Bioinformatics (S.H., J.W.), Department of Biostatistics, Center for Clinical Epidemiology and Biostatistics (M.E.P.), and Penn Cardiovascular Institute (J.M.G., M.S.P., J.A.E., E.E.M., K.B.M., T.P.C.), University of Pennsylvania School of Medicine, Philadelphia.

^* To whom correspondence should be addressed. E-mail: thomas.cappola{at}uphs.upenn.edu.

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.

Key words: genomics • heart failure • hypertrophy • remodeling • transcription factors

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