John Westhone

My laboratory studies how the chromatin microenvironment regulates gene expression while maintaining a stable genome. We interrogate this relationship by studying the role of histone modifying enzymes in both human culture and model systems. We have initiated these types of studies by focusing on a specific class of chromatin regulators, JmjC-containing histone demethylases, that I discovered. Since this discovery, my laboratory has started screening both solid and hematopoietic cancer for genomic anomalies in this class of enzymes. We have uncovered the first enzyme (KDM4A- histone tri-demethylase) responsible for generating site-specific copy gain and are addressing the genomic features that are responsible for increasing the propensity of these regions to copy gain and rereplication during S phase. Additionally, we have begun examining KDM4A at the molecular, biochemical and in vivo level. We have established that KDM4A genetic variants and protein expression levels are important determinants in drug response. We are evaluating these aspects in tumors that have altered copy number and develop drug resistance. Our findings have prompted us to interrogate these same relationships with other chromatin/epigenetic modifiers (lysine methyltransferases and demethylases) and tumors drug response as well. Our discoveries have significant implications in understanding tumor copy number heterogeneity and drug response across cancers, especially in hematologic malignancies, lung, ovarian, renal and breast cancer. These studies have broad implications for cancer therapy and mechanisms of genome instability and drug resistance.

POSITIONS AND HONORS

Positions and Employment

1999 – 2002 Graduate Researcher, Laboratory of Dr. Larry H. Matherly

Wayne State University, Department of Pharmacology

Thesis Project: Identify the transcriptional mechanisms regulating the expression of human reduced folate carrier in normal and malignant tissue.

2002 – 2007 Postdoctoral Fellow, Laboratory of Dr. Yang Shi

Harvard Medical School, Department of Pathology

Projects:

  1. Determine the role of chromatin modifiers in cell fate and differentiation using C. elegans as a model organism.
  2. Identify novel histone demethylases and/or novel chromatin regulators.

2007 – 2014 Assistant Geneticist, Department of Medicine, Massachusetts General Hospital, Boston, MA

2007 – 2014 Assistant Professor, Department of Medicine, Harvard Medical School, Boston, MA

2014 – 2018 Associate Geneticist, Department of Medicine, Massachusetts General Hospital, Boston, MA

2014 – 2018 Associate Professor, Department of Medicine, Harvard Medical School, Boston, MA

2018 – Professor, Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA

2018 – Cancer Epigenetics Program Leader, Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA