Inferring the Role of Enhancer Code in Regulation of Gene Expression

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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.