Cancer epigenetics: Understanding histone methylation in leukemia stem cells

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DESCRIPTION (provided by applicant): 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 "signatures" 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. PUBLIC HEALTH RELEVANCE: Epigenetics is a phenomenon of phenotypic changes caused by alterations that occur on a specific type of DNA-associated protein termed as histone. Epigenetic mechanisms play critical roles in regulating gene expression and defining cellular states, as well as contributing to the onset and development of human pathologies such as cancers. In this project, we focus on some types of leukemia that accounts for a large percentage of human blood cancer patients. However these cases are currently incurable. Investigating the role of affected histone modifier enzymes in tumor prevention will shed light on novel oncogenic mechanisms. It also has clinical significance for cancer diagnosis and therapies. In vitro enzymology established in the study can be adopted in the future for studies of other cancerous alternations and also for screening small molecular inhibitors. For example, one therapeutic idea is to target an unwanted 'hyperactive' histone methyltransferase activity in cancer cells. Importantly, many chromatin modifier enzymes are considered as feasible targets for screening inhibitor chemicals. In summary, studying the molecular basis of epigenetic regulation will promote greater understanding of the development of normal tissue and/or tumors, which in turn, helps to design some novel effective therapeutic intervention for human cancers.