EAGER: Cracking the histone code with engineered histone readers

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Histones are central to genome and organism biology in all eukaryotes. Histone post-translational chemical modifications underlie a “code" translated by proteins with histone reader domains, which provide the critical link between the information maintained in the distribution of histone post-translational modifications and higher-order biological processes (e.g. gene expression, DNA repair). To understand this histone code, we aim to accelerate the discovery of specific interactions between genomes and histone reader domains. New technologies have revolutionized our ability to study genomes at the sequence level. Yet, our understanding of genome biology lags behind due to a more limited toolkit when it comes to measuring the proteins that interact with genomes. This work aims to develop a new method that, if successful, would serve as a broadly applicable tool for measuring the activity of different reader domains across the genome, under different environments, and across development. We envision the deployment of this tool as a potentially transformative framework for studying chromatin biology in diverse organisms. Our lab is also committed to promoting diversity and inclusion in STEM. The preliminary work discussed and proposed work will continue to provide opportunities to undergraduate researchers through the NSF California Alliance for Minority Participation (CAMP) Scholars program. We will attempt a new but untested method to measure genome-wide targeting by histone readers. We will test the approach through the study of histone modifications and readers involved in DNA repair and organism development. This work aims to advance a unified understanding of how histone modifications are translated into higher-order biological information via proteins that bind them by histone readers. If successful, this work will yield a broadly useful system to help decipher how histones orchestrate genome and organism biology. The proposed method could eventually underlie more reliable epigenome diagnostic tools from agriculture to human health.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.