Putt Mary E, Hannenhalli Sridhar, Lu Yun, Haines Philip, Chandrupatla Hareesh R, Morrisey Edward E, Margulies Kenneth B, Cappola Thomas P
Department of Biostatistics and Epidemiology, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Circ Cardiovasc Genet. 2009 Jun;2(3):212-9. doi: 10.1161/CIRCGENETICS.108.816686. Epub 2009 Mar 31.
Pathological 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 understood. Here, we use genomic data to examine the evidence that 5 candidate TF families coregulate gene expression in human heart failure.
RNA isolates from failing (n=86) and nonfailing (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 9076 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 coregulation. 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 the highest odds ratios noted for genes containing both MEF2 and NFAT binding motifs together in the same promoter region (peak odds ratio, 3.47; P=0.005).
These findings provide genomic evidence for coregulation 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 insight into human cardiovascular disorders.
病理应激通过协同作用激活多种心脏转录因子（TFs），在动物模型中诱发心力衰竭。然而，人们对人类心力衰竭中TFs之间的相互作用了解较少。在此，我们利用基因组数据来检验5个候选TF家族在人类心力衰竭中共同调节基因表达的证据。
从衰竭的（n = 86）和非衰竭的（n = 16）人类心脏中分离出的RNA与Affymetrix HU133A阵列进行杂交。对于阵列上的每个基因，我们使用人鼠序列比对和TRANSFAC数据库，在-1-kb启动子区域内确定保守的MEF2、NFAT、NKX、GATA和FOX结合基序。在心脏中表达的9076个基因中，TF结合基序倾向于在特定基因启动子内以非随机模式聚集在一起（P值范围从10^(-2)到10^(-21)），提示共同调节。然后，我们将差异表达建模为启动子区域中存在的TF组合的函数。几种组合预测了衰竭心脏中差异表达可能性的增加，在同一启动子区域同时包含MEF2和NFAT结合基序的基因的优势比最高（峰值优势比，3.47；P = 0.005）。
这些发现为MEF2和NFAT在人类心力衰竭中共同调节心肌基因表达提供了基因组证据。在此过程中，它们将基因表达的组合调节模式扩展到人类心脏，并确定了用于机制研究的新靶基因。更广泛地说，我们展示了整合多种基因组数据源如何产生对人类心血管疾病的新见解。
