Conundrums in Transcriptional Regulation

描述（由申请人提供）：真核基因转录的机制理解是生物学中的一个重要的长期目标，因为它涉及人类健康。生物技术的进步揭示了迄今为止未知的转录调控的复杂性，挑战了现有的模型，并提出了新的问题。拟议中的项目通过新的方法和分析解决了三个这样的问题，并有望提高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，其中一组基因在长进化距离上具有保守的表达，但基因表达的转录机制已经分化。了解这种重新布线的机制对我们理解生物体的进化性和鲁棒性具有重要意义。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，并表征促进重新布线的条件。(2)虽然传统上，一个特定的转录因子（TF）被认为是结合到一个特定的DNA基序，现在它是显而易见的，许多TF可能会识别不同的基序，调节功能不同的结果。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)许多重要的发育增强子都是在距离靶基因多达一百万个核苷酸的地方起作用的。增强子如何实现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有影响。在具体目标3中，我们将开发将增强子映射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