Bipotential lineage determination by EKLF

描述（由申请人提供）：巨核细胞和红系细胞被认为在造血分化过程中源自共同的祖细胞。虽然一些转录调节因子对这一过程很重要，但它们不能解释双电位结果。我们最近通过功能获得和丧失的研究、表达谱分析和分子分析表明，EKLF是一种转录因子，其在红细胞基因调控中的作用已得到很好的确立，在红细胞室建立之前，在红细胞和巨核细胞谱系决定中起着意想不到的指导作用。因此，我们建议通过以下方式扩展这些研究：（1）检查EKLF功能获得和丧失对巨核细胞-红系祖细胞所做的双能谱系决定的影响;（2）确定EKLF调节巨核细胞基因阻遏的机制，遵循交叉拮抗细胞内模型的预测。公共卫生相关性这些研究与阐明哺乳动物造血过程中调节双能决定并导致特定谱系定型的细胞内机制有关。因此，它们与依赖于祖细胞的最佳扩增以用于医学应用的临床研究相关。 我们有新的证据表明，我们确定的一种特定的转录因子可能在造血的特定阶段对祖细胞/后代的决定起着关键作用，并希望确定它是如何实现这一点的。

DESCRIPTION (provided by applicant): Megakaryocytes and erythroid cells are thought to derive from a common progenitor during hematopoietic differentiation. Although a number of transcriptional regulators are important for this process, they do not explain the bipotential result. We have recently shown by gain- and loss-of-function studies, expression profiling, and molecular analyses that EKLF, a transcription factor whose role in erythroid gene regulation is well established, plays an unexpected directive role in erythroid and megakaryocyte lineage decisions prior to establishment of the red cell compartment. We thus propose to extend these studies by: (1) examining the effect of EKLF gain- and loss-of-function on the bipotential lineage decisions made by the megakaryocyte-erythroid progenitor; (2) determining the mechanism by which EKLF regulates megakaryocyte gene repression, following the predictions made by a cross-antagonistic intracellular model. PUBLIC HEALTH RELEVANCE These studies are relevant to delineating the intracellular mechanisms that regulate bipotential decisions during mammalian hematopoiesis and result in commitment to specific lineages. Consequently, they are relevant to clinical studies that depend on optimal expansion of progenitors for their use in medical applications. We have novel evidence that a particular transcription factor that we identified may play a critical role in progenitor/progeny decisions during a specific stage in hematopoiesis, and would like to determine how it accomplishes this.