Published Online
on March 31, 2009

A more recent version of this article appeared on June 1, 2009

This Article Full Text (PDF) Data Supplement All Versions of this Article: 2/3/212    most recent CIRCGENETICS.108.816686v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Putt, M. E. Articles by Cappola, T. P. Search for Related Content PubMed Articles by Putt, M. E. Articles by Cappola, T. P. Related Collections Congestive Functional genomics Gene expression Genomics Physiological and pathological control of gene expression

Original Article

Evidence for co-regulation of myocardial gene expression by MEF2 and NFAT in human heart failure

Mary E. Putt; Sridhar Hannenhalli; Yun Lu; Philip Haines; Hareesh R. Chandrupatla; Edward E. Morrisey; Kenneth B. Margulies and Thomas P. Cappola¹

University of Pennsylvania School of Medicine, Philadelphia, PA

¹ E-mail: thomas.cappola{at}uphs.upenn.edu

Background—Pathologic stresses induce heart failure in animal models through activation of multiple cardiac transcription factors (TFs) working cooperatively. However, interactions among TFs in human heart failure are less well understood. Here we use genomic data to examine the evidence that five candidate TF families co-regulate gene expression in human heart failure.

Methods and Results—RNA isolates from failing (n=86) and non-failing (n=16) human hearts were hybridized with Affymetrix HU133A arrays. For each gene on the array, we determined conserved MEF2, NFAT, NKX, GATA, and FOX binding motifs within the -1 kb promoter region using human-murine sequence alignments and the TRANSFAC database. Across 9,076 genes expressed in the heart, TF binding motifs tended to cluster together in nonrandom patterns within promoters of specific genes (P-values ranging from 10^-2 to 10^-21), suggesting co-regulation. We then modeled differential expression as a function of TF combinations present in promoter regions. Several combinations predicted increased odds of differential expression in the failing heart, with highest odds ratios noted for genes containing both MEF2 and NFAT bindings motifs together in the same promoter (peak OR 3.47, P=0.005).

Conclusions—These findings provide genomic evidence for co-regulation of myocardial gene expression by MEF2 and NFAT in human heart failure. In doing so, they extend the paradigm of combinatorial regulation of gene expression to the human heart and identify new target genes for mechanistic study. More broadly, we demonstrate how integrating diverse sources of genomic data yields novel insights into human cardiovascular disorders.

Key Words: genes • heart failure • hypertrophy • genomics • transcription factors