Johnathan R. Whetstine, PhD
Associate Professor of Medicine
Harvard Medical School
The Whetstine laboratory is interested in understanding 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 C. elegans models. We have initiated these types of studies by focusing on a specific class of chromatin regulators, the JmjC-containing histone demethylases. Since the discovery of these chromatin regulators, my laboratory has started screening tumors for genomic anomalies (copy changes and mutations) in this class of enzyme. Additionally, we have begun examining their molecular roles at a biochemical, molecular and in vivo level. Based on our observations, we are determining whether these genomic alterations will allow us to modify conventional chemotherapy to treat tumors with alterations in JmjC enzymes and establishing whether these changes will serve as novel molecular diagnostics. In addition, we have uncovered an important role for these enzymes in regulating both cell cycle and copy number control and have initiated a number of studies to expand upon this recent discovery. The laboratory is currently expanding these same types of studies into other novel chromatin regulators such as histone methyltransferases and deacetylases.
Johnathan R. Whetstine, PhD
Principal InvestigatorGroup Members
Histone methylation and acetylation dynamics: impact on development and cancer pathology
Events within the nucleus are governed by a number of processes, but increasing information emphasizes the relationship between post-translational modifications (PTMs) on the histones within the chromatin and proper developmental patterning and pathologies like cancer. The N-terminal tails of histones are subject to a plethora of PTMs including phosphorylation, ubiquitination, acetylation and methylation. Each modification can affect chromatin architecture, but the sum of these modifications may be the ultimate determinant of the chromatin state and biological outcome. Research has shown that multiple lysine (K) residues on the tails of histone H3 and H4 are sites for methylation. The site and degree of methylation (mono-, di-, or tri-) are linked to transcriptional activation and repression, cell cycle progression, and DNA damage response. Many biological processes like heterochromatin formation and X-inactivation are regulated by histone methylation; therefore, aberrant methylation can result in human diseases such as cancer. For this reason, organisms have developed enzymes that are responsible for both adding and removing the methyl mark. Our group studies the impact that histone-modifying proteins have on development, behavior and cancer pathology.
My laboratory is focused on understanding the impact that both methylation and acetylation dynamics have in both human cell culture and C. elegans. In particular, we are investigating the impact that the histone 3 lysine 9/36 tri-demethylases have on differentiation, neural behavior and tumorigenesis by understanding their roles in transcriptional regulation of the coding and noncoding regions of the genome, in cell cycle progression through regulating chromatin structure, and in the stability of the genome. We are also interrogating the mechanisms associated with regulating histone demethylase function. Our most recent studiesFor example, we have demonstrated that KDM4A is modulated throughout the cell cycle by the SCF E3 ubiquitin ligase complex, which is an importantan important regulator of demethylase levels and function during the cell cycle. Most recently, we have demonstrated that JMJD2A/KDM4A is amplified in a number of tumors, correlates with poor outcome in ovarian cancer patients and regulates the site-specific copy gain of regions implicated in chemotherapy resistance. Through the use of proteomics and genomics, we have been able to identify important associated proteins regulating these KDM4A driven events at regions being directly modulated.
The laboratory will interrogate the functional role of histone demethylases by using genomic (ChIP-chip, ChIP-seq, microarrays, and RNA-seq), proteomic (MS-MS complexes and PTMs), cytological (live imaging and deconvolution confocal microscopy) and genetic (C. elegans, human cell lines, and zebrafish) approaches. Using these strategies, we have uncovered roles for the C. elegans JMJD-2 enzyme in genomic stability and DNA replication. We have extended these studies to demonstrate a conserved role for human JMJD2A in DNA replication and demonstrated that ubiquitin plays a key role in this regulation. Using similar approaches, we have also uncovered an important link between histone deacetylase 1 (HDAC-1) and the regulation of extracellular matrix biology in both humans and C. elegans, a finding that has direct implications in cancer chemotherapy. Overall, the laboratory will integrate a number of approaches and systems to determine the important biological pathways regulated by histone demethylases and histone deacetylases.
Long term goal
Our long-term goal is to use our studies about histone modifiers to provide insights into the development of better molecular diagnostics, epigenetic therapeutic molecules, or use of novel therapeutic combinations so that a better efficacy can be achieved in the treatment of cancer or neurological disease.
Postdoctoral Fellow (1)
My laboratory is focused on understanding the impact that both methylation and acetylation dynamics has in both human cell culture and C. elegans. In particular, the laboratory is investigating the impact that the histone 3 lysine 9/36 tri-demethylases [JMJD2A-D; Whetstine et al., (2007) Cell 125: 467-81] have on tumorigenesis, transcriptional regulation, and genomic integrity. The laboratory will interrogate the role of these enzymes by using genomic, proteomic, cytological and genetic approaches. Similar approaches allowed an important link to be established for histone deacetylase 1 (HDAC-1) and the regulation of extra-cellular matrix biology in both human and C. elegans, which has direct implications in cancer chemotherapy [Whetstine et al., (2005) Mol. Cell 18:483-90]. The laboratory will continue to investigate the functional overlap or unique pathways that the C. elegans class I histone deacetylases regulate by using the same type of approaches. Overall, the laboratory will integrate a number of approaches and systems to determine the important biological pathways regulated by histone demethylases and histone deacetylases. The laboratory is looking for highly motivated, tenacious scientists that are enthusiastic, team players and love science. The laboratory is looking for researchers with documented proficiency in any of the following areas (basic molecular biology, protein biochemistry, genomics, epigenetics, C. elegans, cytology, development biology, DNA damage and repair) but interested in learning new approaches or systems to answer the exciting questions before us. Requirements: For these positions a PhD and/or MD is required. These positions require enthusiastic, self motivated, independent thinkers with strong interpersonal skills, and the ability to communicate with laboratory members, national and international collaborators.
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