The post-translational modification of histone proteins is now established as an important mechanism for regulating gene expression in eukaryotic cells. However, a structural and mechanistic understanding of how the histone modification enzymes function on their nucleosome substrate is lacking. This shortcoming limits interpretation of the wealth of genetic, genomic and biochemical data available, and it hampers development of new therapeutics that target the many chromatin enzymes associated with human diseases including cancer. We are focused on addressing these deficiencies through structure determination of histone modification enzymes bound to their physiological nucleosome substrate. We propose to determine X-ray crystal structures of histone modification enzymes associated with human diseases in complex with the nucleosome, using established and novel approaches to crystallize these complicated, multicomponent protein/DNA complexes. We will complement our crystallographic efforts with use of cryoelectron microscopy for three-dimensional structure determination of chromatin enzyme/nucleosome complexes. We also plan to use cryoelectron microscopy to tackle structure determination of native, megadalton sized histone modification enzyme complexes.

Public Health Relevance

In our cells, our DNA genetic information is packaged with histone proteins into chromatin. Recent studies have shown that histone proteins can be decorated by histone modification enzymes with small molecules or proteins, and these decorations regulate gene expression in normal and diseased cells. Our studies will visualize how different histone modification enzymes associated with stem cells and cancer perform their functions.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Unknown (R35)
Project #
1R35GM127034-01
Application #
9486072
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Preusch, Peter
Project Start
2018-09-01
Project End
2023-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Pennsylvania State University
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
003403953
City
University Park
State
PA
Country
United States
Zip Code
16802