Conundrums in Transcriptional Regulation

描述（由申请人提供）：了解真核基因转录的机制是生物学中一项重要的长期目标，因为它关系到人类健康。生物技术的进步揭示了迄今为止未知的转录调控复杂性，挑战了当前的模型并提出了新的问题。拟议的项目通过新颖的方法和分析解决了三个这样的问题，并承诺加强我们对转录控制的理解。(1)现在有几个已知的“网络重新布线”的例子，在这些例子中，一组基因在漫长的进化距离中保持了表达，但基因表达的转录机制却出现了分歧。了解这种重新布线的机制对我们理解生物体的可进化性和健壮性具有重要意义。在具体目标1中，我们将开发计算方法来识别转录网络重新布线的实例，并描述促进重新布线的条件。(2)虽然传统上认为特定的转录事实（TF）与特定的DNA基序结合，但现在越来越明显的是，许多TF可能识别不同的基序，这些基序调节不同的功能结果。在具体目标2中，我们将开发计算方法来发现和表征转录因子结合位点的功能亚类。(3)许多重要的发育促进因子在距离靶基因100万个核苷酸之外起作用。增强子如何完成其远距离作用尚不完全清楚，这对我们理解发育和组织特异性基因调控具有重要意义。在具体目标3中，我们将开发将增强子定位到其远端靶基因的方法。1

DESCRIPTION (provided by applicant): A mechanistic understanding of eukaryotic gene transcription is an important long-term goal in biology as it pertains to human health. Biotechnological advances have revealed heretofore unknown complexity of transcriptional regulation, challenging current models and raising new questions. The proposed projects address three such questions via novel methods and analysis, and promise to enhance our understanding of transcriptional control. (1) There are now a several known examples of "network rewiring" where a group of genes have conserved expression over long evolutionary distances but the transcriptional mechanisms underlying the expression of the genes has diverged. Understanding the mechanisms for such rewiring has implications for our understanding of evolvability and robustness of organisms. In the specific aim 1, we will develop computational methods to identify instances of transcriptional network rewiring and characterize the conditions facilitating the rewiring. (2) While traditionally, a particular transcription facto (TF) was believed to bind to a specific DNA motif, now it is becoming apparent that many TFs may recognize distinct motifs that modulate functionally distinct outcomes. In the specific aim 2, we will develop computational methods to discover and characterize functional subclasses of transcription factor binding sites. (3) Many important developmental enhancers act from a distance, up to a million nucleotides away from the target gene. How the enhancers accomplish their action-at-a-distance is not entirely clear and has implications for our understanding of developmental and tissue-specific gene regulation. In the specific aim 3 we will develop methods to map enhancers to their distal target genes. 1