Identification of gene co-regulatory modules and associated cis-elements involved in degenerative heart disease.
Identification of gene co-regulatory modules and associated cis-elements involved in degenerative heart disease.
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DOI：
10.1186/1755-8794-2-31
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发表时间：
2009-05-28
影响因子：
2.7
通讯作者：
Pertsov AM
中科院分区：
文献类型：
--
作者：
Danko CG;Pertsov AM
心肌病是一种心肌退行性疾病，是发达国家的主要死亡原因之一。对心肌疾病的微阵列研究已经确定了多达数百个基因，这些基因随着疾病的进展而显著改变其表达模式。然而，推动这些变化的调控机制，特别是涉及的转录因子网络，仍然知之甚少。我们的目标是(A)确定在不同类型的心肌病中经历相似表达变化的共同调节基因的模块，以及(B)揭示组成这些模块的基因的近端启动子区域中转录因子结合位点的特定模式，顺式元件。我们分析了149个来自不同病因的肥厚型和扩张型心肌病的基因芯片样本。系统聚类法和基因本体论注释用于识别表达高度相关和具有相似生理功能的基因丰富的模块。为了发现可能在表达上发生潜在变化的基序，我们使用了三个最有趣的模块中基因的启动子区域作为基序发现算法的输入。所得到的模体被用来构建一个概率模型，预测不同心肌病的表达变化。我们发现，功能丰富程度最高的三个模块包含涉及心肌收缩(n=9)、能量产生(n=20)或蛋白质翻译(n=20)的基因。利用基序发现工具发现，收缩模块中的基因包含一个TATA盒和一个CACC盒，并且在其他富含GC的基序中缺失；而翻译模块中的基因包含一个富含嘧啶的启动子ELK-1、SP-1和一个带有GCGC核心的新基序。使用朴素贝叶斯分类器发现，基序模式是对表达模式的统计预测，优势比为2.7(收缩)、1.9(能量产生)和5.5(蛋白质翻译)。我们确定了由假定的顺式调控基序组成的模式，这些顺式调控基序丰富在基因的上游启动子序列中，这些基因在继发于各种病因的心肌病的表达上经历了类似的变化。我们的分析是了解转录因子网络在退行性心脏病期间活跃地调节基因表达的第一步。
Cardiomyopathies, degenerative diseases of cardiac muscle, are among the leading causes of death in the developed world. Microarray studies of cardiomyopathies have identified up to several hundred genes that significantly alter their expression patterns as the disease progresses. However, the regulatory mechanisms driving these changes, in particular the networks of transcription factors involved, remain poorly understood. Our goals are (A) to identify modules of co-regulated genes that undergo similar changes in expression in various types of cardiomyopathies, and (B) to reveal the specific pattern of transcription factor binding sites, cis-elements, in the proximal promoter region of genes comprising such modules. We analyzed 149 microarray samples from human hypertrophic and dilated cardiomyopathies of various etiologies. Hierarchical clustering and Gene Ontology annotations were applied to identify modules enriched in genes with highly correlated expression and a similar physiological function. To discover motifs that may underly changes in expression, we used the promoter regions for genes in three of the most interesting modules as input to motif discovery algorithms. The resulting motifs were used to construct a probabilistic model predictive of changes in expression across different cardiomyopathies. We found that three modules with the highest degree of functional enrichment contain genes involved in myocardial contraction (n = 9), energy generation (n = 20), or protein translation (n = 20). Using motif discovery tools revealed that genes in the contractile module were found to contain a TATA-box followed by a CACC-box, and are depleted in other GC-rich motifs; whereas genes in the translation module contain a pyrimidine-rich initiator, Elk-1, SP-1, and a novel motif with a GCGC core. Using a naïve Bayes classifier revealed that patterns of motifs are statistically predictive of expression patterns, with odds ratios of 2.7 (contractile), 1.9 (energy generation), and 5.5 (protein translation). We identified patterns comprised of putative cis-regulatory motifs enriched in the upstream promoter sequence of genes that undergo similar changes in expression secondary to cardiomyopathies of various etiologies. Our analysis is a first step towards understanding transcription factor networks that are active in regulating gene expression during degenerative heart disease.
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影响因子：
5.8
作者：
Holland, R. C. G.;Down, T. A.;Pocock, M.;Prlic, A.;Huen, D.;James, K.;Foisy, S.;Draeger, A.;Yates, A.;Heuer, M.;Schreiber, M. J.
通讯作者：
Schreiber, M. J.
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
24
作者：
Barth, Andreas S.;Kuner, Ruprecht;Sueltmann, Holger
通讯作者：
Sueltmann, Holger
影响因子：
5.3
作者：
CHRISTENSEN, TH;PRENTICE, H;KEDES, L
通讯作者：
KEDES, L
影响因子：
37.8
作者：
Flesch, M;Margulies, KB;Mann, DL
通讯作者：
Mann, DL