The Whetstine laboratory studies how chromatin factors control gene expression and genome stability. These types of studies were initiated by studying a specific class of chromatin regulators, JmjC-containing histone demethylases, that Dr. Whetstine was involved in discovering. While interrogating demethylase function, the Whetstine laboratory uncovered the first enzyme (KDM4A- histone tri-demethylase) responsible for generating extrachromosomal transient site-specific copy gains (TSSGs) of drug resistant oncogenes. Dr. Whetstine’s team is further interrogating these same relationships with other chromatin/epigenetic modifiers and DNA amplification events occurring in cancer and other diseases. His laboratory aims to provide mechanistic insights into extrachromosomal DNA amplification generation and the associated heterogeneity within cell populations, while identifying biomarkers to both predict and target copy gain events driving human diseases (Figure 1). The Whetstine laboratory is addressing the genomic features (epigenome and 3D genome organization) that are responsible for increasing the propensity of regions to rereplicate and amplify during S phase. Similar studies are also being conducted to better understand the role that chromatin control has in modulating DNA replication, transcription and genome integrity. The laboratory leverages a range of cytological, biochemical, genomic and epigenomic approaches to address DNA amplification control and DNA replication.

The Whetstine laboratory also addresses whether modulation of epigenetic factors provides novel therapeutic options across tumors (e.g., conventional chemotherapy and immune checkpoint therapy). His team is evaluating the expression levels, copy gains or losses, mutational and polymorphic repertoire in malignancies, as well as posttranslational regulatory mechanisms for epigenetic factors and how they relate to various tumor types. The Whetstine laboratory evaluates the impact that these events have on drug response and ability to stratify patients. These studies resulted in the identification of KDM4A associated copy gains as described above, as well as the identification of novel enzyme function for demethylases and association with chemotherapeutic response in lung cancer. Comparable studies are now being extended into additional chromatin modifying enzymes.

https://www.foxchase.org/johnathan-whetstine