Inferring the Role of Enhancer Code in Regulation of Gene Expression

顺式调控逻辑是DNA调控元件中的代码，它控制着染色质和基因功能的可及性和亲和性。最近对转录因子（tf）占用和组蛋白标记的大规模全基因组定位为了解后生动物的大量顺式调控元件提供了重要的见解。然而，细胞机制解释顺式调控代码以设置染色质的可及性和亲和性的方式在很大程度上仍然未知。在这里，我提出了一个研究计划，将通过绘制在正常细胞分化过程中增强子与基因的相互作用来推断顺式调控代码。我的建议将测试以下假设：(1)增强子的动态参与/脱离是组织特异性和发育性基因的标志；(2)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）途径的广泛耦合；(3)选择microRNA途径沉默基因导致“顺式调控衰减”，并伴随增加目标基因3'UTR的复杂性。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协调染色质亲和景观和调节基因表达输出的理解。该程序产生的数据将显著增强我们对顺式调控代码和基因调控网络组织在细胞分化和发育过程中的作用的认识。

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.