Proteins interact with genomic DNA to bring the genome to life. The precise regulation of numerous genes is required to maintain normal cellular proliferation and differentiation. A key step in the regulation of networks that control gene expression is the sequence-specific binding of transcription factors to their DNA recognition sites, and sequence-specific DNA binding by proteins even controls recombination, restriction, and replication. Understanding where regulatory proteins bind to the genome in vivo is critical to understanding the mechanism and logic of these essential processes. Available methods to determine sequence requirements suffer from either insufficient specificity, sensitivity or a limited potential for multiplexed analysis.
Therefore, I w ill develop a highly parallel and sensitive method for studying the sequence specificity of DNA-protein interactions. My approach will be based on the sensitive proximity ligation assay developed in my host laboratory and will include a multiplexed readout using tag arrays. This technique will allow functional analysis of DNA binding proteins at an unprecedented scale and with the potential to analyse even individual cells, providing a unique perspective on gene regulation.
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