Epistasis of Transcriptomes Reveals Synergism between Transcriptional Activators Hnf1α and Hnf4α
Epistasis of Transcriptomes Reveals Synergism between Transcriptional Activators Hnf1α and Hnf4α
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DOI：
10.1371/journal.pgen.1000970
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发表时间：
2010-05-01
期刊：
影响因子：
4.5
通讯作者：
Ferrer, Jorge
中科院分区：
文献类型：
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作者：
Boj, Sylvia F.;Petrov, Dimitri;Ferrer, Jorge
单个基因的转录是由DNA结合转录因子之间的组合相互作用所决定的。当前的挑战是要理解这种组合相互作用是如何调控构成细胞功能和疾病基础的广泛遗传程序的。转录因子Hnf1α和Hnf4α控制胰岛β细胞的功能和生长，它们基因的突变会导致密切相关类型的糖尿病。我们现在利用基因上位性来研究Hnf1α和Hnf4α在胰岛中是如何功能性相互作用的。对来自Hnf1a(+/-)或胰腺特异性Hnf4a突变小鼠的胰岛进行的表达谱分析表明，这两种转录因子调控着一组极为相似的基因。我们整合了表达和基因组结合研究，并表明这两种突变模型共有的转录表型与共同的直接靶标相关，而非与已知的Hnf1α对Hnf4a基因转录的影响相关。对单突变和双突变胰岛转录组的上位性分析显示，Hnf1α和Hnf4α对共同靶标具有协同调控作用。在Hnf4a缺陷型胰岛中，Hnf1α在某些选定靶标上的结合减少，但在其他靶标上保持不变，这表明协同调控的机制是基因特异性的。这些发现提供了一种体内研究组合基因调控的策略，并揭示了Hnf1α和Hnf4α是如何控制在人类单基因糖尿病中存在缺陷的一种常见胰岛细胞调控程序的。
The transcription of individual genes is determined by combinatorial interactions between DNA-binding transcription factors. The current challenge is to understand how such combinatorial interactions regulate broad genetic programs that underlie cellular functions and disease. The transcription factors Hnf1 alpha and Hnf4 alpha control pancreatic islet beta-cell function and growth, and mutations in their genes cause closely related forms of diabetes. We have now exploited genetic epistasis to examine how Hnf1 alpha and Hnf4 alpha functionally interact in pancreatic islets. Expression profiling in islets from either Hnf1a(+/-) or pancreas-specific Hnf4a mutant mice showed that the two transcription factors regulate a strikingly similar set of genes. We integrated expression and genomic binding studies and show that the shared transcriptional phenotype of these two mutant models is linked to common direct targets, rather than to known effects of Hnf1 alpha on Hnf4a gene transcription. Epistasis analysis with transcriptomes of single-and double-mutant islets revealed that Hnf1 alpha and Hnf4 alpha regulate common targets synergistically. Hnf1 alpha binding in Hnf4a-deficient islets was decreased in selected targets, but remained unaltered in others, thus suggesting that the mechanisms for synergistic regulation are gene-specific. These findings provide an in vivo strategy to study combinatorial gene regulation and reveal how Hnf1 alpha and Hnf4 alpha control a common islet-cell regulatory program that is defective in human monogenic diabetes.