My long-term research interest is to investigate epigenetic mechanisms in oncogenesis. Epigenetics is a phenomenon for phenotypic changes caused by DNA sequence-independent alterations such as chromatin modification. The literature has documented a collection of cancerous deregulations that appear specifically to interfere with proper histone modification. Our focus is recurrent chromosomal translocation found in human leukemia, which targets molecular players that regulate a specific chromatin modification? histone H3 tri-methylated at lysine 4 (abbreviated as H3K4Me3). H3K4Me3 is a prominent histone mark associated with euchromatin structure and active transcription. MLL, an H3K4me3-specific methyltransferase enzyme, is a famed leukemia oncogene, and gain-of-function mutation of MLL represents one of the most common aberrations in human leukemia. In keep with these observations, our recent studies demonstrate that a leukemic translocation NUP98-JARID1A disrupts and/or imparts dominant negative effect on H3K4Me3-specific histone demethylases JARID1. As a result, aberrant accumulation of H3K4Me3 marks on a number of oncogenes leads to their transactivation. Our preliminary data also suggests that such a novel epigenetic mechanism transforms normal hematopoietic stem cells (HSCs) to leukemia-initiating stem cells (LSCs). JARID1A was initially isolated as factor to interact with tumor suppressor RB. We hypothesize that JARID1 family histone demethylases, which were found down regulated among human leukemia, belong to a novel class of tumor suppressors in leukemias. During the mentored phase, I will utilize genomic approaches to identify the histone methylation ?sigatures? that are associated with LSCs and HSCs. A parallel objective in this phase is to establish targeted mouse ES cells that harbor JARID1A/1B inactivation alleles, as well as to develop techniques for in vitro histone enzymology. In the independent phase, I will examine in vivo functions of JARID1 histone demethylases in tumor suppression and/or normal development using knockout mouse models. Active JARID1 enzymes (in form of protein complexes) and their mediated histone demethylation in vitro will also be characterized. An excellent environment and complementary training program provided by laboratories of Dr. David Allis (mentor), Dr. Shahin Rafii (co-mentor), collaborators, and an Advisory Committee will facilitate my research in the mentored phase and ensure a smooth transition to an independent investigator. The proposed research at the independent phase (Year 3-5) will pave the road to launch my future investigation to reveal novel epigenetic mechanisms in oncogenesis and identify ?druggable'targets for novel therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Transition Award (R00)
Project #
5R00CA151683-06
Application #
8710047
Study Section
No Study Section (in-house review) (NSS)
Program Officer
Okano, Paul
Project Start
2012-09-01
Project End
2015-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Biochemistry
Type
Schools of Medicine
DUNS #
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Lu, Rui; Wang, Ping; Parton, Trevor et al. (2016) Epigenetic Perturbations by Arg882-Mutated DNMT3A Potentiate Aberrant Stem Cell Gene-Expression Program and Acute Leukemia Development. Cancer Cell 30:92-107
Chen, Chun-Wei; Armstrong, Scott A (2015) Targeting DOT1L and HOX gene expression in MLL-rearranged leukemia and beyond. Exp Hematol 43:673-84
Wang, Gang Greg; Konze, Kyle D; Tao, Jianguo (2015) Polycomb genes, miRNA, and their deregulation in B-cell malignancies. Blood 125:1217-25
Xu, Bowen; On, Doan M; Ma, Anqi et al. (2015) Selective inhibition of EZH2 and EZH1 enzymatic activity by a small molecule suppresses MLL-rearranged leukemia. Blood 125:346-57
Zhang, Zhi-Min; Rothbart, Scott B; Allison, David F et al. (2015) An Allosteric Interaction Links USP7 to Deubiquitination and Chromatin Targeting of UHRF1. Cell Rep 12:1400-6
Xu, Bowen; Konze, Kyle D; Jin, Jian et al. (2015) Targeting EZH2 and PRC2 dependence as novel anticancer therapy. Exp Hematol 43:698-712
Cai, Ling; Rothbart, Scott B; Lu, Rui et al. (2013) An H3K36 methylation-engaging Tudor motif of polycomb-like proteins mediates PRC2 complex targeting. Mol Cell 49:571-82
Konze, Kyle D; Ma, Anqi; Li, Fengling et al. (2013) An orally bioavailable chemical probe of the Lysine Methyltransferases EZH2 and EZH1. ACS Chem Biol 8:1324-34
Lu, Rui; Wang, Gang Greg (2013) Tudor: a versatile family of histone methylation 'readers'. Trends Biochem Sci 38:546-55
Kumar, Ganesan Senthil; Chang, William; Xie, Tao et al. (2012) Sequence requirements for combinatorial recognition of histone H3 by the MRG15 and Pf1 subunits of the Rpd3S/Sin3S corepressor complex. J Mol Biol 422:519-31