Uncovering promoter-type-specific transcriptional activators

Animal genomes contain thousands of genes, each of which contains the instructions for some of the basic building blocks of cells. These building blocks termed proteins can perform highly diverse functions and confer unique properties to different cell types. Different cell types are therefore different in form and function by activating only distinct sets of genes from the genome they all share. This differential gene expression starts with transcription, the process of copying the genomic DNA into RNA by the enzyme Polymerase II. For each gene, transcription starts at the genes promoter region and promoters in mammals come in three main types, or which one the TATA-box promoters has been particularly well studied, while the others, including the most abundant CpG island (CGI) promoters, are much less well characterized. In particular, the machinery of protein factors that activate the different promoter types is unknown and which activators are specific to each of the promoter types remain elusive. This project aims to identify new transcriptional activators specific to CGI, TCT, and TATA-box promoters, utilizing mouse embryonic stem cells (mESCs) as the model. A newly-developed functional recruitment assa will be employed to assay thousands of proteins for their ability to activate transcription from different promoters in mESCs. The project anticipates to uncover novel promoter-specific activators that will be subsequently validated and their endogenous gene-regulatory functions as well as mechanisms of activation will be determined. By bridging genomics, molecular biology, biochemistry and bioinformatics, the research not only aims to significantly enhance our knowledge about promoter-specific activators but also aspires to decipher their gene-regulatory roles in an unprecedented manner. The knowledge gained will further our understanding of gene regulation, genome and developmental biology in mammals with substantial implication for our understanding of human biology and disease.