Inferring the Role of Enhancer Code in Regulation of Gene Expression

顺式调控逻辑是DNA调控元件中的编码，其控制染色质和基因功能的可及性和亲和力景观。最近大规模的全基因组范围内的转录因子（TF）的占有率和组蛋白标记的映射提供了重要的见解到庞大的剧目的后生动物顺式调控元件。然而，顺式调节密码被细胞机制解释以设置染色质的可及性和亲和力景观的方式仍然在很大程度上未知。在这里，我提出了一个研究计划，将推断的顺式调控编码映射增强子在正常细胞分化过程中的基因相互作用。我的建议将测试以下假设：（i）增强子的动态接合/脱离是组织特异性和发育基因的标志，（ii）基因调控网络利用染色质重塑介导的基因调控和非编码（RNAi）途径的广泛偶联，以及（iii）用于沉默基因的microRNA途径的选择导致“顺式调控衰变”。以及伴随的靶基因3 'UTR复杂性的增加。我希望从这个项目中获得的知识将大大提高我们对基因调控网络如何发挥作用以协调染色质的亲和力景观和调控基因表达输出的理解。从这个程序产生的数据将显着提高我们的知识顺式调控代码的作用和组织的基因调控网络在细胞分化和发展。

The cis-regulatory logic is the code in the DNA regulatory elements that governs the accessibility and affinity landscape of chromatin and gene function. Recent large-scale genome-wide mapping of transcription factors (TFs) occupancy and histone marks have provided important insights into the vast repertoire of the metazoan cis-regulatory elements. However, the manner in which the cis-regulatory code is interpreted by the cellular machinery to set the accessibility and the affinity landscape of chromatin remains largely unknown. Here, I propose a research program that will infer the cis-regulatory code by mapping enhancer to gene interaction during normal cellular differentiation. My proposal will test the hypotheses that (i) dynamic engagement/disengagement of enhancers is a hallmark of tissue-specific and developmental genes, (ii) Gene regulatory networks utilize extensive coupling of chromatin-remodeling mediated gene regulation and noncoding (RNAi) pathway and (iii) selection of microRNA pathway for silencing genes results in "cis-regulatory decay" and concomitant increase in complexity of the 3'UTR of the target genes. I expect that knowledge gained from this project will significantly enhance our understanding of how gene regulatory networks function to orchestrate affinity landscape of chromatin and regulate gene expression output. Data generated from this program will significantly enhance our knowledge on the role of cis-regulatory code and the organization of gene regulatory networks during cellular differentiation and development.