CAREER Exploiting missense histone mutations to explore mechanisms of gene regulation

Emory University, Atlanta GA

Investigators

Abstract

Each cell within an organism contains identical genetic information, but the precise regulation of this information dictates gene expression and biological function. Part of regulating gene expression is accomplished by the packaging of the genome into chromatin. The nucleosome forms the repeating chromatin unit, a complex of DNA and two copies each of histones H3, H4, H2A, and H2B. Histone variants and histone posttranslational modifications (PTMs) are key regulators of nucleosome accessibility and chromatin remodeling, supporting changes to gene expression. This gene regulation is fundamentally important to how organisms function and respond to environmental cues and is highlighted by the prevalence of histone mutations associated with human disease. This project will leverage computational and wet-lab research with yeast and human model systems to examine mechanisms by which naturally occurring histone mutations dysregulate gene expression. This work will advance our understanding of the role of histone variants in nucleosome integrity, chromatin modification, and gene expression. The project itself provides opportunities to engage scientific trainees as part of “Team Histone,” assembled of high school, undergraduate, graduate, and post-doctoral trainees to build scientific agency and provide research and educational experiences to a broad set of participants within STEM fields. Genetic studies demonstrate the importance of conserved and essential histone amino acids for maintaining nucleosome structure and function as well as proper regulation of gene expression. However, how most missense histone mutations impact histone structure and function is currently unknown. This project identified a series of recurrent histone missense mutations in human disease. In silico modeling suggests that some of these histone mutations impart local structural changes that alter transcription, and studies in yeast have defined diverse growth and cellular phenotypes. The major aims of this project are to use mammalian and yeast models, along with molecular, cellular, and computational biology to define the mechanism(s) by which the changes alter histone/nucleosome function and delineate the biological outcome of mutant histone expression in model organisms and cells. By exploiting histone mutations to explore histone protein function, nucleosome remodeling, and regulation of gene expression, this project will broadly advance the understanding of how histone proteins contribute to the maintenance of appropriate nucleosome structure and function, to contribute to cell and organismal fitness. 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.