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Johnathan R. Whetstine, PhD

Johnathan Whetstine
About

Research Program

Key Awards

Lung Cancer Discovery Award
American Lung Association
2014, 2017, 2019

 

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.

Key publications highlighting discoveries from the Whetstine Laboratory:

  • Black, J.C., Manning, A., Van Rechem, C., Kim, J., Ladd, B., Cho, J., Pineda, C.M., Murphy, N., Daniels, D.L., Montagna, S., Lewis, P.W., Glass, K., Allis, C.D., Dyson, N.J., Getz, G., Whetstine, J.R. (2013) H3K9/36me3 Demethylase KDM4A Promotes Site-Specific Copy Gain and Re-replication of Regions Amplified in Tumors. Cell. 154, 541-555. PubMed PMID: 23871696; PubMed Central PMCID: PMC3832053.
  • Black, J.C., Atabakhsh, E., Kim J., Biette K.B., Van Rechem C., Ladd B., Burrowes P.d., Donado C., Mattoo H., Kleinstiver B.P., Song B., Andriani G., Joung J.K., Iliopoulos O., Montagna C., Pillai S., Getz G., Whetstine J.R. (2015) Hypoxia drives transient site-specific copy gain and drug-resistant gene expression. Genes and Development 29, 1018-1031. PubMed PMID: 25995187; PubMed Central PMCID: PMC4441050.
  • Van Rechem, C., Black, J.C., Greninger, P., Zhao, Y., Donado, C., Burrowes, P.D., Ladd, B., Christiani, D.C., Benes, C.H., and Whetstine, J.R. (2015) A Coding Single Nucleotide Polymorphism in Lysine Demethylase KDM4A Associates with Increased Sensitivity to mTOR Inhibitors. Cancer Discov. 5, 245-254. PubMed PMID: 25564517; PubMed Central PMCID: PMC4355226.
  • Mishra, S., Van Rechem, C., Pal, S., Clarke, T.L., Chakraborty, D., Mahan, S., Black, J.C., Murphy, S.E., Lawrence, M.S., Daniels, D.L., Whetstine, J.R. (2018) Cross-talk between Lysine-Modifying Enzymes Controls Site-Specific DNA Amplifications. Cell 174, 803-817. PubMed PMID: 30057114; PubMed Central PMCID: PMC6212369.
  • Clarke, T.L., Tang, R., Chakraborty, D., Van Rechem, C., Ji, F., Mishra, S., Ma, A., Kaniskan, H.U., Jin, J., Lawrence, M.S., Sadreyev, R.I., Whetstine, J.R. (2020) Histone Lysine Methylation Dynamics Control EGFR DNA Copy Number Amplification. Cancer Discov. 10, 306-325.PubMed PMID: 31776131.
Cancer Discovery, February 2020
An issue and review describing: Methylation- A Multifaceted Modification
Lysine Demethylase 4A (KDM4A) regulates translation and impacts mTOR therapeutic response
Hypoxia Controls Epigenetic Programs Driving Amplification
MicroRNAs Control site-specific copy gains
There is an epigenetic addressing system for defining site-specific DNA rereplication and amplifications
Education and Training

Educational Background

  • Postdoctoral Fellow, Epigenetics/Pathology, Harvard Medical School, Cambridge, MA, 2002-07
  • PhD, Pharmacology, Wayne State University, Detroit, MI, 2002
  • Graduate Researcher, Laboratory of Dr. Larry H. Matherly, Department of Pharmacology, Wayne State University, Detroit, MI 1999-2002

Memberships

  • American Association for Cancer Research
  • American Society of Biochemist and Molecular Biologist 

Honors & Awards

  • Lung Cancer Discovery Award, American Lung Association, 2014, 2017, 2019
  • Keynote Molecular Analysis for Personalized Therapy, 2016
  • MGH One Hundred,  Massachusetts General Hospital, 2016
  • Innovation Award, Alex Lemonade Stand Foundation, 2015
  • Leukemia and Lymphoma Society Scholar, The Leukemia and Lymphoma Society, 2014
  • Tepper Family MGH Research Scholar, Massachusetts General Hospital, 2014
  • Basic Research Scholar Award, American Cancer Society, 2013
  • Howard M. Goodman Prize, MGH, 2009
  • New Scholar Award, Ellison Medical Foundation, 2009
Research Profile

Research Program

Lab Overview

whetstinelab.com

Epigenetic Mechanisms Driving Copy Gain, Amplifications and Drug Resistance

  • We are asking what cellular cues or exposures are involved in driving copy gain of regions promoting drug resistance and tumorigenesis. These same questions are being extended to other clinically relevant amplified oncogenes. 
  • We are identifying all known signaling and epigenetic-related pathways involved in driving copy gain and amplifications.
  • We are identifying the epigenetic states associated with the genome that have a propensity to undergo copy number changes.
  • We are screening for factors that will allow these copy gains to be inherited.
  • We are collaborating with clinicians to establish the optimal patients for using epigenetic therapies targeting pathways promoting copy gain and drug resistance.
 
Epigenetic Mechanisms Impacting Cancer Therapy

  • We are assessing whether there are other chromatin regulators involved in protein synthesis.
  • We are determining whether other chromatin factors enhance mTOR inhibitor sensitivity or other cancer therapies.
  • We are studying other coding SNPs in chromatin modifiers that impact drug response and patient stratification.
  • We use genetic features or molecular mechanisms downstream of chromatin regulators to stratify and optimally treat cancer patients. 
 
Epigenetic Mechanisms Regulating Cell Cycle Progression

 

  • We are using next generation sequencing strategies to map the epigenome during cell cycle.
  • We are identifying chromatin and non-coding RNAs that are regulating cell cycle progression.​
Publications

Selected Publications

Capucine Van Rechem, Fei Ji, Sweta Mishra, Damayanti Chakraborty, Sedona E. Murphy, Megan E. Dillingham, Ruslan I. Sadreyev, Johnathan R. Whetstine, The lysine demethylase KDM4A controls the cell-cycle expression of replicative canonical histone genes, Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, Volume 1863, Issue 10, 2020, 194624

Clarke T.L., Tang R., Chakraborty D., Van Rechem C., Ji F., Mishra S., Ma A., Kaniskan H.U., Jin J., Lawrence M.S., Sadreyev R.I., Whetstine J.R., Histone lysine methylation dynamics control egfr DNA copy number amplification. Cancer Discov, 2019. 26.370

Etchegaray J.P., Zhong L., Li C., Henriques T., Ablondi E., Nakadai T., Van Rechem C., Ferrer C., Ross K.N., Choi J.E., Samarakkody A., Ji F., Chang A., Sadreyev R.I., Ramaswamy S., Nechaev S., Whetstine J.R., Roeder R.G., Adelman K., Goren A., Mostoslaysky R., The histone deacetylase sirt6 restrains transcription elongation via promoter-proximal pausing. Mol Cell. 75(4): 683-699 e7, 2019. 14.548

Whetstine J.R., Prc2 plays red light, green light with mhc-i and cd8(+) t cells. Cancer Cell. 36(4): 343-345, 2019. 23.916

Mishra S, Van Rechem C, Pal S, Clarke TL, Chakraborty D, Mahan SD, Black JC, Murphy SE, Lawrence MS, Daniels DL, Whetstine JR.
Cross-talk between Lysine-Modifying Enzymes Controls Site-Specific DNA Amplifications, Cell. 2018 Aug 9

Guarner, A., Morris, R., Korenjak, M., Boukhali, M., Zappia, M.P., Van Rechem, C., Whetstine, J.R.,
Ramaswamy, S., Zou, L., Frolov, M.V., Haas, W., Dyson, N.J. (2017) E2F/DP Prevents Cell-Cycle
Progression in Endocycling Fat Body Cells by Suppressing dATM Expression. Dev. Cell 43, 689-703.

Mishra, S., and Whetstine, J.R. (2016) Different Facets of Copy Number Changes: Permanent,
Transient, and Adaptive. Molecular and Cellular Biology 36, 1050-1063

Denu, J. (2016) Expression level of the histone demethylase KDM4A is regulated by microRNAs. J.
Biol. Chem. 291

Black, J.C., Zhang, H., Kim, J., Getz, G., and Whetstine, J.R. (2016) Regulation of Transient Sitespecific
Copy Gain by MicroRNA. J. Biol. Chem. 291, 4862-4871

Black, J.C., Atabakhsh, E., Kim J., Biette K.B., Van Rechem C., Ladd B., Burrowes P.d., Donado C.,
Mattoo H., Kleinstiver B.P., Song B., Andriani G., Joung J.K., Iliopoulos O., Montagna C., Pillai S., Getz
G., Whetstine J.R. (2015) Hypoxia drives transient site-specific copy gan and drug-resistant gene
expression. Genes and Development 29, 1018-1031

Heinrichs, A. (2013) Chromatin affects Copy Gain. NSMB. 20, 1025.

Aranda, V. (2013) Unraveling chromatin checkpoints. Nat. Med. 19, 1102.

KDM4A Promotes Site-Specific Copy Number Gain (2013) CD-RW2013-162

Kiberstis, P.A. (2013) Gains in Cancer Epigenetics. Science. 341, 696.

Rickels, R., and Shilatifard, A. (2013) A Histone Modifier’s Ill-Gotten Copy Gains. Cell. 154, 477-479.

Black, J.C., Manning, A., Van Rechem, C., Kim, J., Ladd, B., Cho, J., Pineda, C.M., Murphy, N.,
Daniels, D.L., Montagna, S., Lewis, P.W., Glass, K., Allis, C.D., Dyson, N.J., Getz, G., Whetstine, J.R.
(2013) H3K9/36me3 Demethylase KDM4A Promotes Site-Specific Copy Gain and Re-replication of
Regions Amplified in Tumors. Cell. 154, 541-555. NIHMS525115

Lan, F., Bayliss, P. E.*, Rinn, J. L.*, Whetstine, J. R.*, Wang, J. K., Chen, S., Iwase, S., Alpatov, R.,
Issaeva, I., Canaani, E., Roberts, T. M., Chang, H. Y., and Shi, Y. A histone H3 lysine 27 demethylase regulates animal posterior development. Nature 2007; 449: 689-694. * Contributed Equal to this study.

Chen, Z.*, Zang, J.*, Whetstine, J. R., Hong, X., Davrazou, F., Kutateladze, T. G., Simpson, M., Mao,
Q., Pan, C-H., Dai, S., Hagman, J., Hansen, K., Shi, Y., and Zhang, G. (2006) Crystal Structure of the
Catalytic Core Domain of a Novel Histone Demethylase. Cell, 125, 691-702. * Contributed Equal to this study. 

Whetstine, J. R., Nottke, A., Lan, F., Huarte, M., Smolikov, S., Chen, Z., Spooner, E., Li, E., Zhang, G.,
Colaiacovo, M., and Shi, Y. (2006) Reversal of histone lysine trimethylation by the JMJD2 family of histone demethylases. Cell, 125, 467-481.

Shi, Y., Lan, F., Matson, C., Mulligan, P., Whetstine, J. R., Cole, P. A., Casero, R. A., and Shi, Y.
(2004) Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell, 119, 941-953.

Additional Publications

Dr. Whetstine on PubMed

Cancer Discovery, February 2020
An issue and review describing: Methylation- A Multifaceted Modification
Lysine Demethylase 4A (KDM4A) regulates translation and impacts mTOR therapeutic response
Hypoxia Controls Epigenetic Programs Driving Amplification
MicroRNAs Control site-specific copy gains
There is an epigenetic addressing system for defining site-specific DNA rereplication and amplifications

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