Nate Hathaway, Ph.D., an assistant professor in the UNC Eshelman School of Pharmacy, has received a grant worth more than $1.5 million over five years from the National Institute of General Medical Sciences to investigate the mechanism of HP1-mediated heterochromatin assembly and durability in live cells.
“Proper regulation of chromatin, the material that makes up chromosomes, is required for human development,” Hathaway said “Abnormalities or impairment in the regulation of chromatin modification pathways lies at the root of many human cancers.”
Hathaway is an assistant professor in the Division of Chemical Biology and Medicinal Chemistry and a member of the School’s Center for Integrative Chemical Biology and Drug Discovery and the UNC Lineberger Comprehensive Cancer Center.
Heterochromatin protein-1 is overexpressed, meaning overproduced, in a number of human cancers, and elevated HP1 levels correlate with lower survival rates for patients with breast and prostate cancer. Heterochromatin has a different density than normal chromatin and works to suppress or modify the activity of genes.
This NIGMS grant will allow Hathaway to examine the fundamental mechanisms of HP1-mediated gene repression to better understand the mechanics of its role in development and disease. He said he also plans to develop new small-molecule inhibitors of the HP1 pathway that could serve as lead compounds for future therapeutics.
Hathaway’s team will examine how the influence of chromatin structural features, such as promoter transcriptional activity, DNA methylation and histone posttranslational modifications, affect heterochromatin assembly, as well as the influence these same chromatin features have on the durability of heterochromatin gene repression.
To understand how these regulatory processes function in live organisms, Hathaway’s group has developed a novel platform that allows individual chromatin modifying activities such as heterochromatin protein-1 to be recruited with high temporal control to native chromatin substrates. They recently improved this system to allow them to rapidly change the structure of the endogenous chromatin substrate in order to explore the regulation of a range of promoter and gene structures. The long-term goal of this project is to understand the mechanism of HP1-mediated gene repression and to determine the key features that provide heterochromatin stability through successive cell generations.
Additionally, using high throughput screening in collaboration with the School’s Center for Integrative Chemical Biology and Drug Discovery, Hathaway’s team has discovered novel inhibitors that disrupt HP1 mediated gene repression. They will develop these small molecule probes and use them to define the role of individual enzymatic activities in heterochromatin assembly and durable gene repression. At the conclusion of these studies, using a combination of chemical approaches and novel in vivo tools, Hathaway will provide a new generalizable model for how HP1-mediated heterochromatin is assembled and maintained in living cells. This new model will be applied in future work from his lab to understand the role of heterochromatin gene regulation in human cancer.