Hannenhalli Sridhar, Putt Mary E, Gilmore Joan M, Wang Junwen, Parmacek Michael S, Epstein Jonathan A, Morrisey Edward E, Margulies Kenneth B, Cappola Thomas P
Department of Genetics and Penn Center for Bioinformatics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Circulation. 2006 Sep 19;114(12):1269-76. doi: 10.1161/CIRCULATIONAHA.106.632430. Epub 2006 Sep 4.
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.
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.
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.
在心力衰竭的小鼠模型中，特定转录因子（TFs）可调节心脏基因表达，但它们在人类受试者中的相关性仍未得到验证。我们开发并应用了一种称为转录基因组学的计算方法，以检验一组离散的心脏TFs与人类心力衰竭相关的假设。
将来自衰竭（n = 196）和非衰竭（n = 16）人类心脏的RNA分离物与Affymetrix HU133A芯片杂交，确定差异表达的心力衰竭基因。然后利用公共基因组序列数据库确定这些心力衰竭基因的-5-kb启动子序列中过度表达的TF结合位点。在人类心力衰竭基因的启动子中，在小鼠心力衰竭模型中鉴定出的TF（MEF2、NKX、NF-AT和GATA）的结合位点显著过度表达（P<0.002；错误发现率2%至4%）。此外，FOX TF的结合位点在晚期人类和早期小鼠心力衰竭中均显示出大量过度表达（每组P<0.002，错误发现率<4%）。FOXC1、C2、P1、P4和O1A在衰竭的人类心肌细胞中的表达水平与已确定的肥大TF相似，以及衰竭的人类心肌细胞核中存在丰富的FOXP1蛋白，进一步支持了FOX TF的作用。
我们的结果首次证明，在小鼠模型中鉴定出的特定TF（MEF2、NKX、NFAT和GATA）与人类心力衰竭相关。此外，这些数据表明FOX TF家族的特定成员（FOXC1、C2、P1、P4和O1A）在心力衰竭发病机制中以前未被提及。这些发现提供了动物模型与人类疾病之间的关键联系，并表明FOX信号在调节人类心脏对压力的肥大反应中具有特定作用。
