Johnathan R. Whetstine
Department of Medicine
Massachusetts General Hospital Cancer Center
Building 149, 13th Street, Room 7-213
Charlestown, MA 02129
Tel: (617) 643-4374
Fax: (617) 724-9648
Web Page: The Whetstine Lab Page
The Impact Histone Methylation and Acetylation Dynamics Has On Development and Cancer Pathology
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 (Figure 1 A). 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 (Figure 1 B). 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 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. 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. Our long term goal is to use these findings to provide insights into the development of better epigenetic therapeutic molecules or to use combinatorial therapy so that a better efficacy can be achieved in the treatment of cancer.
- Whetstine, J. R., Ceron, J., Ladd, B., Dufourcq, P., Reinke, V., and Shi, Y. (2005) Regulation of tissue-specific and extracellular matrix-related genes by a class I histone deacetylase. Mol. Cell 18, 483-490. 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. and Whetstine, J.R. (2007) Dynamic Regulation of Histone Lysine Methylation by Demethylases. Mol. Cell, 12, 1-14.
- Lan F, Bayliss PE, Rinn JL, Whetstine JR, Wang JK, Chen S, Iwase S, Alpatov R, Issaeva I, Canaani E, Roberts TM, Chang HY, Shi Y. (2007) A histone H3 lysine 27 demethylase regulates animal posterior development. Nature. 449: 689-694.
- Iwase S, Lan F, Bayliss P, de la Torre-Ubieta L, Huarte M, Qi HH, Whetstine JR, Bonni A, Roberts TM, Shi Y The X-linked mental retardation gene SMCX/JARID1C defines a family of histone H3 lysine 4 demethylases. Cell. 03/26/2007; 6(6); 1077-88.
- Chen Z, Zang J, Kappler J, Hong X, Crawford F, Wang Q, Lan F, Jiang C, Whetstine J, Dai S, Hansen K, Shi Y, Zhang G Structural basis of the recognition of a methylated histone tail by JMJD2A. Proc Natl Acad Sci U S A. 06/28/2007; 26(26); 10818-23.
BBS webpage updated 12/02/2009