Genes in higher organisms (i.e., animals, plants and fungi) are packaged into chromatin. Chromatin is a complex formed by the winding of DNA around proteins called histones. It has two important functions: to efficiently package DNA to fit inside the small volume of the cell’s nucleus and to regulate access to the genetic information encoded in the DNA. Despite the well-established link between chromatin remodeling and gene expression, how histones and the structure of chromatin control access to DNA remains elusive. This project will directly address some long-standing questions in DNA packaging that are fundamental to understanding multiple aspects of molecular and cellular biology. In conjunction with the research activity, the investigator will develop a graduate-level course to provide students with hands-on training in cryo-electron microscopy (EM). In additional, the investigator will provide training opportunities for high-school teachers and students to gain the knowledge and skills needed to delve into advanced topics in molecular biology. This will be achieved through two outreach programs focused on using Molecular Graphic Tools to explore the public protein databases.
Histone variants are isoforms of canonical histones, representing one or a few amino acid differences in their protein sequences. Histone variants have specific expression and localization patterns in cells. Incorporation of histone variants is known to be a major mechanism in regulating chromatin structure and function. Nevertheless, the understanding of histone variant-dependent chromatin regulation is limited by the knowledge gap in how variant-specific changes in protein sequence are translated into specific function. In this project, the investigators will use a combination of cryo-EM, biochemistry, and biophysical methods to investigate the mechanism-of-action of three histone variants: variant H2A.Z, H3.3 and macroH2A. The project will reveal the structural basis of how chromatin structure and DNA accessibility are modulated by these variants alone and by their interplay with non-histone proteins. This work will also provide valuable insights into the diverse roles of these variants in transcriptional control in cells.
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.
