The role of MOZ in normal and leukemic hematopoiesis

描述（由申请人提供） 分化的造血祖细胞表现出有序的成熟， 染色质，一个进程，提供了独特的形态线索， 细胞的身份和成熟阶段。 这些核变化， 在光镜下，可以反映造血细胞基因表达的变化， 干细胞在分化为各种成熟的 造血谱系 然而，越来越清楚的是， 染色质结构的变化不仅反映了 转录因子的形成及其信号通路 回答。 相反，针对染色质重塑的变化有助于确定 基因表达的全局模式，可以遗传的模式， 随着每个细胞周期而增强。 许多重要的造血调节因子 由于它们参与白血病相关的染色体 易位 MOZ基因位于染色体8 p11带，参与 三个独立的骨髓性白血病易位 MOZ伴侣基因 分别被t（8;16）、t（8;22）和inv（8）破坏的是CREB结合 16 p13的CBP蛋白、22 q13的P300蛋白和8 q13的TIF 2（NCoA-2）蛋白; 伴侣是组蛋白乙酰转移酶和核受体辅助调节剂。 MOZ是一种假定的组蛋白乙酰转移酶（HAT），是 HAT MYST家族，一个包括参与细胞增殖的蛋白质的家族 周期调节、染色质重塑和剂量补偿。 MOZ的 结构表明，像CBP/P300和HAT的其他成员一样， MOZ超家族中，MOZ参与蛋白质复合物， 转录活性和染色质结构。 该提案测试了 假设MOZ是组蛋白乙酰转移酶， 在造血过程中起重要作用的辅助调节因子。 破坏 染色体易位的MOZ基因被认为是干扰 关键的造血信号通路，破坏骨髓生成， 导致急性髓细胞白血病的发展。 的具体目标 该建议是：1）表征MOZ在胚胎发育期间的表达， 发育、造血和使用北方印迹的细胞周期， 免疫印迹、原位杂交和免疫组织化学; 2）评估 MOZ的共调节功能，以及它对完整的 乙酰转移酶活性，使用瞬时和逆转录病毒介导的稳定 在造血细胞中的转染测定和显微注射研究， 非造血细胞;以及3）定义正常功能的破坏如何 MOZ影响小鼠胚胎发育和造血， 破坏MOZ基因。 该项目的长期目标是 了解MOZ如何有助于承诺和终端差异化 在造血过程中。

DESCRIPTION (provided by applicant) Differentiating hematopoietic progenitors demonstrate an orderly maturation of chromatin, a progression that provides distinctive morphologic cues as to a cell's identity and stage of maturity. These nuclear changes, visible under the light microscope, mirror the changes in gene expression that hematopoietic stem cells undergo as they differentiate towards the various mature hematopoietic lineages. However, it is becoming increasingly clear that changes in chromatin structure do not merely reflect the molecular decision making of transcription factors and the signaling pathways to which they respond. Rather, changes directed at chromatin remodeling help to determine global patterns of gene expression, patterns which can be inherited and enhanced with each cell cycle. Many important hematopoietic regulators have been identified due to their involvement in leukemia-associated chromosomal translocations. The MOZ gene, situated at chromosomal band 8p1l, is involved in three independent myeloid leukemia translocations. MOZ partner genes disrupted by t(8;16), t(8;22), and inv(8) are, respectively, the CREB binding protein (CBP) at 16p13, P300 at 22q13, and TIF2 (NCoA-2) at 8q13; all three partners are histone acetyltransferases and nuclear receptor coregulators. MOZ is a putative histone acetyltransferase (HAT) and the founding member of the MYST family of HATs, a family that includes proteins involved in cell cycle regulation, chromatin remodeling, and dosage compensation. MOZ's structure suggests that, like CBP/P300 and other members of the HAT superfamily, MOZ participates in protein complexes that modulate both transcriptional activity and chromatin structure. This proposal tests the hypothesis that MOZ is a histone acetyltransferase and transcriptional coregulator that plays an important role during hematopoiesis. Disruption of the MOZ gene by chromosomal translocations is proposed to interfere with critical hematopoietic signaling pathways, disrupt myelopoiesis, and contribute to the development of acute myeloid leukemia. The specific aims of this proposal are to 1) characterize MOZ expression during embryonic development, hematopoiesis, and the cell cycle using northern blotting, western blotting, in situ hybridization, and immunohistochemistry; 2) assess MOZ's coregulatory functions, and its dependence on an intact acetyltransferase activity, using transient and retroviral-mediated stable transfection assays and microinjection studies in hematopoietic and non-hematopoietic cells; and 3) define how disruption of the normal functions of MOZ affects murine embryonic development and hematopoiesis using targeted disruption of the MOZ gene. The long term goal of this project is to understand how MOZ contributes to commitment and terminal differentiation during hematopoiesis.