The influence of the ZXDC protein on myelopoiesis

描述(申请人提供)：造血由复杂的基因转录因子网络控制，以确保脊椎动物所有类型血细胞的发育和维持。造血所必需的许多转录因子的功能障碍与不同类型的白血病以及先天性细胞减少症有关。这项建议的长期目标是确定锌指X-连锁重复C(ZXDC)基因影响骨髓生成的机制。ZXD家族成员ZXDC至少与髓系细胞发育过程中的两个关键转录因子相互作用：PU.1和Gfi1。利用髓系分化模型，ZXDC被发现参与嗜酸性粒细胞的发育，并可能在维持祖细胞状态方面发挥作用。这个试点项目有两个目标：(1)确定ZXDC在利用人类原代细胞进行骨髓生成中的作用；(2)通过整合的基因组筛选，使用表达谱和染色质免疫沉淀，然后再使用微阵列(芯片)来识别可能的ZXDC靶基因。这些数据将扩大控制髓系细胞发育的基因调控网络，识别参与这一过程的ZXDC调控基因，并为全面分析ZXDC在造血中的作用机制提供基础。 与公共卫生相关：控制人类多种血细胞发育的机制是复杂的。当这些机制功能不正确时，它们可能会促进白血病的发展。这项拟议的研究是为了表征一种新发现的蛋白质家族--转录因子家族ZXD--影响血细胞发育的机制。

DESCRIPTION (provided by applicant): Hematopoiesis is controlled by an intricate network of gene transcription factors, to ensure the development and maintenance of all types of blood cells in vertebrates. Dysfunction of many of the transcription factors necessary for hematopoiesis is associated with different types of leukemias as well as congenital cytopenias. The long term objective of this proposal is to identify the mechanisms by which the zinc finger X-linked duplicated C (ZXDC) gene affects myelopoiesis. One ZXD family member, ZXDC, interacts with at least two key transcription factors in myeloid cell development: PU.1 and Gfi1. Using models of myeloid differentiation, ZXDC was found to participate in eosinophil development and may also have a role in maintaining progenitor status. This pilot project has two goals: (1) characterize the role of ZXDC in myelopoiesis employing human primary cells and (2) identify putative ZXDC target genes by an integrated genomic screen employing expression profiling and chromatin immunoprecipitation followed by microarray (ChIP- chip). These data will expand the gene regulatory network controlling myeloid cell development, identify genes regulated by ZXDC involved in this process and provide the foundation for a comprehensive mechanistic analysis of ZXDC function in hematopoiesis. PUBLIC HEALTH RELEVANCE: The mechanisms that control the development of the many types of blood cells in humans are complex. When these mechanisms function incorrectly, they can contribute to the development of leukemia. The proposed research is to characterize the mechanisms by which a newly identified family of proteins, the transcription factor family ZXD, affects the development of blood cells.