Massachusetts General Hospital | Cancer Center

Program Affiliations

• Center for Cancer Research

Johnathan R. Whetstine, PhD
Assistant Professor of Medicine
Harvard Medical School

Research Summary

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 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. The laboratory is currently expanding these types of studies into other novel chromatin regulators such as histone methyltransferases and deacetylases.

Visit the Whetstine Lab website.

Johnathan R. Whetstine, PhD
Principal InvestigatorGroup Members

• Joshua C. Black, PhD
• Lily Gantchev
• Christine Kim   
• Brendon Ladd, PhD
• Hailey Park
• Daniel Perez
• Cristiana Pineda, BS
• Capucine Van Rechem, PhD
• Johnathan R. Whetstine, PhD
• Will Wiswall, MS

Research Projects

Histone Methylation and Acetylation Dynamics: Impact on Development and Cancer Pathology

Image courtesy of Johnathan Whetstine, PhD

Background

Events within the nucleus are governed by a number of processes, but an ever increasing amount of information is emphasizing 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 total sum of these modifications may be the ultimate determinant of the chromatin state and biological outcome. Multiple lysine (K) residues on the tails of histone H3 and H4 have been shown to be sites for methylation. The site and degree of methylation (mono-, di-, or tri-) are linked to both transcriptional activation and repression, as well as 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 is focused on studying the impact that histone modifying proteins have on both development and cancer pathology.

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 [Figure 1C, JMJD2A-D; Whetstine et al. (2006) Cell 125: 467-81] have on differentiation, neural behavior and tumorigenesis by understanding their roles in transcriptional regulation of the coding and non-coding regions of the genome, in cell cycle progression through regulating chromatin structure (Black et al. (2010) Mol Cell 40: 736-48) and in the stability of the genome (Whetstine et al. (2006) Cell 125: 467-81). We are also interrogating the mechanisms associated with regulating histone demethylase function.

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 approaches we have uncovered roles for the C. elegans JMJD-2 enzyme in genomic stability and DNA replication (Whetstine et al. (2006) Cell 125: 467-81 and Black et al. (2010) Mol Cell 40: 736-48). We have extended these studies to demonstrate a conserved role for human JMJD2A in DNA replication. Using similar approaches, we have also uncovered an important link between 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]. 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

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.

Current areas of active investigation

• Determining the impact that histone modifications and histone demethylases have on chromatin structure and cell cycle progression.
• Uncovering the role of histone demethylases and histone methylation in aging response using C. elegans.
• Identifying interacting proteins for the JMJD2 proteins as well as JMJD2 downstream target regions in the human and C. elegans genome. Use these observations to better understand the role of these enzymes in differentiation, neural behavior, and tumorigenesis.
• Identifying genomic anomalies in histone modifiers and determining if these aberrations impact histone modification patterns, classes and stages of human tumors, and response to chemotherapeutics.

Research Positions

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.

Contact:

Center for Cancer Research
149 13th Street, Room 7-213
Charlestown, MA 02129
E-mail: jwhetstine@hms.harvard.edu

Publications

View a list of publications by researchers at the Whetstine Laboratory

Whetstine Laboratory

Phone: 617-643-4374
Email: jwhetstine@hms.harvard.edu