EZH2 in lymphoid lineage specification and commitment

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DESCRIPTION (provided by applicant): EZH2 is the histone methyltransferase component of the polycomb repressor complex 2 (PRC2), which is required for repression of numerous lineage specifying transcription factors during development. Recent studies have revealed that both gain and loss of function of EZH2 can contribute to lymphoid malignancy. Here we will test the hypothesis that EZH2 is required for commitment of common lymphoid progenitors to the adaptive lymphocyte (B and T cell) fates but not to innate lymphocyte (ILC1 and ILC2) fates. We will test this hypothesis by examining the consequences of Ezh2 inactivation in common lymphoid progenitors under competitive and non-competitive conditions by flow cytometric analysis of lymphoid cells and through the use of in vitro assays that measure both frequency of differentiation and commitment to a given lineage. In parallel we will identify EZH2 target genes by examining the global changes in gene expression in lymphocytes and their progenitors caused by EZH2-deficiency as well as identifying genes that are bound by EZH2 and fail to undergo H3K27 trimethylation, the hallmark of EZH2 activity, in EZH2-deficient cells. Taken together, our study will provide significant insight into the mechanisms controlling gene expression during lymphocyte lineage specification and commitment. In addition, we will gain a better understanding of how EZH2 mutations lead to leukemia and lymphoma and how treatment of these diseases with EZH2 inhibitors might influence normal lymphocyte development.