Research summary

Deregulation of chromatin, the complex of DNA and proteins in the nucleus, has emerged as a common theme in human cancers. Many types of cancers are associated with recurrent mutations in histone modifier genes, chromatin remodeling complex members and transcriptional regulators. The Davis lab studies applies genomic approaches to identify the functional consequences of mutations in cancer.

 

Sarcoma genomics

Chromosomal translocations affecting transcriptional regulators are common occurrences for a range of sarcomas. Using Ewing sarcoma as a model, we have demonstrated that transcription factor chimerism results in genome-wide retargeting associated with alterations in transcription and chromatin accessibility. By examining chromatin accessbility, histone modification and stem cell biology, we are exploring the mechanisms of transcriptional deregulation.

Renal cell carcinoma

SETD2 and PBRM1 are commonly mutated in human clear cell renal cell carcinoma. Using genome-wide, molecular and biochemical approaches we are exploring the chromatin consequences of these mutation. Recently, we have shown that SETD2 mutations results in loss of H3K36me3 which is associated with widespread transcriptional alterations, including intron retention and alternative splicing.

Chromatin at a platform for drug discovery

In a close collaboration with the Center for Integrative Chemical Biology and Drug Discovery in UNC’s Eshelman School of Pharmacy, we are applying chromatin accessibility as a strategy for drug discovery. This project capitalizes on a unique epigenetically-targeted compound library generated and maintained by the Center.

 

Funding

Hyundai Hope on Wheels Foundation

National Cancer Institute

Rita Allen Foundation

V Foundation for Cancer Research

The Wide Open Charitable Foundation

We are also grateful to the many individuals who have contributed to the Davis Lab through the Lineberger Comprehensive Cancer Center or the Department of Pediatrics.