EZH2 in lymphoid lineage specification and commitment

EZH2是多梳抑制物复合体2的组蛋白甲基转移酶组分 (PrC2)，这是抑制许多指定转录的谱系所必需的 发展中的因素。最近的研究表明，无论是收益还是损失， EZH2的功能与淋巴系统恶性肿瘤的发生密切相关。在这里我们将测试 假设EZH2是共同淋巴祖细胞向 适应性淋巴细胞(B和T细胞)命运而不是先天淋巴细胞(ILC1和ILC2) 命运。我们将通过检查Ezh2失活在 竞争性和非竞争性条件下常见淋巴系祖细胞的流动 淋巴细胞的细胞学分析和通过使用体外分析来测量 分化的频率和对给定血统的承诺。同时，我们将 通过检测EZH2基因表达的全球变化来确定EZH2靶基因 EZH2缺乏症所致淋巴细胞及其前体细胞的鉴定 与EZH2结合并未能经历H3K27三甲基化的基因，这是 EZH2活性，在EZH2缺陷细胞中。总而言之，我们的研究将提供有意义的 淋巴细胞谱系基因表达调控机制的研究进展 详细说明和承诺。此外，我们将更好地了解如何 EZH2突变导致白血病和淋巴瘤以及如何治疗这些疾病 EZH2抑制剂可能会影响正常淋巴细胞的发育。

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.