Mechanisms of DNA binding and gene regulation by C2H2 zinc finger proteins

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The genome encodes highly detailed instructions indicating when and where different genes need to be active in the cell. A massively complex network of proteins called “transcription factors” executes these regulatory instructions. Transcription factors regulate the activity of genes by binding to very specific sites on the genome. This remarkable specificity is mediated by their ability to recognize particular “DNA sequences”, words that are made of the DNA alphabet and mark the genomic sites that should be bound by each transcription factor.******With over 700 members, the “C2H2” zinc finger family constitutes the largest class of regulatory proteins. My previous research has shown that the C2H2 proteins recognize the most diverse set of DNA sequences among transcription factors, regulate the activation of a large number of genes, affect various cellular pathways, and have been a driving force in the evolution of the mammalian genome. However, the molecular mechanisms that underlie this functional diversity have only been partially characterized. Our research aims to understand the principles of DNA binding and gene regulation by C2H2 proteins.******Here, we aim to study the molecular mechanisms that allow the C2H2 proteins to recognize diverse DNA sequences. We focus on two aspects of this diversity: (a) the ability of C2H2 proteins to recognize multiple distinct DNA sequences through utilization of different parts of the protein, and (b) their ability to read “epigenetic” marks, a second layer of information that the cell overlays on top of the genetic information in order to precisely control the architecture and the activity of the genome. We will develop novel computational models that connect the structure of C2H2 proteins to the genetic and epigenetic alphabet that they recognize, revealing how regulatory instructions are read and interpreted by these proteins at the molecular level. These models will help us better understand the mechanisms of gene regulation by C2H2 proteins, trace their evolutionary origins, and reveal new functions for them. They will also enable us to predict the molecular functions of previously uncharacterized C2H2 proteins. Given the central role of these proteins in the evolution and function of our genome, these studies will allow us to decipher the fundamental principles that govern our biology.**