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Read the Whetstine Lab 2017-2018 Annual Report
Johnathan R. Whetstine, PhDAssociate Professor of MedicineHarvard Medical School
The Whetstine laboratory is interested in understanding how the chromatin microenvironment regulates gene expression while maintaining a stable genome. Our ultimate goal is to harness this mechanistic understanding to identify novel therapeutic opportunities and to block chemotherapeutic resistance. We integrate biochemistry, genetics, genomics and computation to elucidate chromatin modulators involved in these processes. We have initiated these types of studies by focusing on a specific class of chromatin regulators, the JmjC-containing histone demethylases and histone lysine methyltransferases.
My laboratory screens tumors for genomic anomalies (copy changes and mutations) in these classes of enzymes and examines their molecular roles at a biochemical, molecular and in vivo level. These combined approaches will determine whether tumors with alterations in JmjC enzymes or lysine methyltransferases provide an opportunity to modify conventional chemotherapy, to identify mechanisms of drug resistance and to identify novel molecular diagnostics.
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Johnathan R. Whetstine, PhDPrincipal Investigator
Understanding how epigenetics directly impacts cancer progression and drug response
The N-terminal tails of histones are subject to a plethora of post translational modifications (PTMs). 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. 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 enzymes that are responsible for both adding and removing the methyl marks.
My laboratory investigates how the interplay between the enzymes that are adding lysine methylation (referred to as lysine methyltransferases, KMTs) and removing the methylation states (referred to as lysine demethylases, KDMs) impacts transcriptional and post transcriptional regulation of the genome [Van Rechem et al. (2015) Cancer Discovery and Black et al. (2016) J. Biol. Chem.), cell cycle progression through altering chromatin organization [Black et al. (2010) Mol. Cell and Van Rechem et al. (2011) J. Biol. Chem.], and genome stability Comment [SSK1] (i.e., DNA amplifications and rearrangements) [Black et al. (2013) Cell, Black et al. (2015) Genes and Development, Black et al. (2016) J. Biol. Chem.]. In fact, our group was the first to discover that lysine modifying enzymes and their associated methylate states are critical modulators of site-specific rereplication and DNA amplification of regions promoting drug resistance through their associated gene products [Black et al. (2013) Cell]. These studies have opened an entirely new concept around the modulation of DNA amplification and how these events can occur across and within tumors. We are actively expanding these studies within the group.
This image illustrates the site-specific DNA copy gains that occur upon overexpression or stabilization of the histone 3 lysine 9/36 tri-demethylase KDM4A. The nuclei are white and the genomic regions that undergo copy gains are green, while regions not impacted by KDM4A overexpression or stabilization are in red. Data related to this image are in Black et al (2015) Genes and Development.
While resolving the molecular roles these enzymes play in cancer, we are also uncovering the physiological pathways that directly modulate the activity, stability and function of these enzymes. For example, these studies have allowed us to better understand how types of cell stress or signaling events impact epigenetic regulators, and in turn, gene expression, DNA amplification and drug response within tumors [Black et al. (2015) Genes and Development]. Understanding the epigenetic mechanisms that influence gene expression and genomic heterogeneity in tumors will allow biomarkers and drug targets to be identified in order to circumvent this major challenge in treating cancer from pediatrics to adults and hematological to solid cancers. This area is of significant interest to the laboratory.
The laboratory uses a range of approaches to interrogate the functional role epigenetic regulators: genomic (ChIP-seq and RNA-seq), proteomic (MS-MS complexes and PTMs), cytologic (live imaging and deconvolution confocal microscopy) and genetic (human cell models and models systems) (lower panel). Using these strategies, we have uncovered a conserved role forJMJD2A in genomic stability and DNA replication [Black et al. (2010) Mol. Cell and Van Rechem et al. (2011) JBC]. Furthermore, we uncovered a conserved role for chromatin states and KDM4A in modulating rereplication at specific sites in the genome. The rereplication promotes site-specific copy gains of drug resistant regions in both human and zebrafish cells [Black et al. (2015) Genes and Development]. This series of discoveries identified the first enzyme, physiological condition and chromatin states that modulate copy gain and selection of drug resistant regions across cancer types. Therefore, combining model systems with human cell culture models as well as integrating multiple approaches, we are poised to uncovered mechanisms impacting genome stability and drug resistant gene selection across tumors.
This image represents the types of approaches that the Whetstine Laboratory is using to understand the impact that chromatin and the associated modulatory factors have on development and cancer.
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.
Center for Cancer Research149 13th Street, Room 7-213Charlestown, MA 02129E-mail: firstname.lastname@example.org
View a list of publications by researchers at the Whetstine Laboratory
Black JC, Zhang H, Kim J, Getz G, Whetstine JR. Regulation of transient site-specific gain by microRNA. J. Biol. Chem. 291, 4862-4871, 2016.
Black JC, Atabakhsh E, Kim J, Biette KB, Van Rechem C, Ladd B, Burrowes Pd, Donado C, Mattoo H, Kleinstiver BP, Song B, Andriani G, Joung JK, Iliopoulos O, Montagna C, Pillai S, Getz G, Whetstine JR. Hypoxia drives transient site-specific copy gain and drug-resistant gene expression. Genes and Development. 29, 1018- 1031, 2015.
Van Rechem C, Black JC, Greninger P, Zhao Y, Donado C, Burrowes Pd, Ladd, B, Christiani DC, Benes CH, Whetstine JR. A Coding Single Nucleotide Polymorphism in Lysine Demethylase KDM4A Associates with Increased Sensitivity to mTOR Inhibitors. Cancer Discov. 5, 245-254, 2015.
Van Rechem C, Black JC, Boukhali M, Aryee MJ, Graslund S, Haas W, Benes CH, Whetstine JR. Lysine Demethylase KDM4A Associates with Translation Machinery and Regulates Protein Synthesis. Cancer Discov. 5, 255-263, 2015.
Black JC, Manning AL, Van Rechem C, Kim J, Ladd B, Cho J, Pineda CM, Murphy N, Daniels DL, Montagna C, Lewis PW, Glass K, Allis CD, Dyson NJ, Getz G, Whetstine JR. KDM4A Lysine Demethylase Induces Site- Specific Copy Gain and Rereplication of Regions Amplified in Tumors. Cell. 154, 541-555, 2013.
Black JC, Allen A, Van Rechem C, Forbes E, Longworth M, Tschöp K, Rinehart C, Quiton J, Walsh R, Smallwood A, Dyson NJ, Whetstine JR. Conserved antagonism between JMJD2A/KDM4A and HP1 during cell cycle progression. Mol Cell. 40(5):736-48, 2010 Dec 10
Video: Drug-resistant lung cancer research funded by the American Lung Association. In this video, Dr. Johnathan Whetstine, Associate Professor of Medicine at Harvard Medical School and Dr. Sweta Mishra, a Postdoctoral Research Fellow discuss their work at Massachusetts General Hospital Cancer Center with drug-resistant lung cancer research and the American Lung Association Research Awards Nationwide. Read more here.
Video: Making strides Against Breast Cancer Kick off breakfast, August 2nd, 2016. Making Strides Against Breast Cancer supporters help the American Cancer Society share in hope,courage, and caring to make the world free from the pain and suffering of breast cancer.
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