Bipotential lineage determination by EKLF

描述（由申请人提供）：巨核细胞和红细胞被认为在造血分化过程中来自一个共同的祖细胞。尽管许多转录调控因子对这一过程很重要，但它们并不能解释双电位的结果。我们最近通过功能获得和功能丧失研究、表达谱分析和分子分析表明，EKLF是一种转录因子，其在红系基因调控中的作用已经确立，在红细胞区室建立之前，在红系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来扩展这些研究：(1)研究EKLF功能的获得和丧失对巨核细胞-红细胞祖细胞双电位谱系决定的影响；(2)根据交叉拮抗细胞内模型的预测，确定EKLF调节巨核细胞基因抑制的机制。这些研究与描述哺乳动物造血过程中调节双电位决定的细胞内机制有关，并导致对特定谱系的承诺。因此，它们与临床研究相关，这些研究依赖于祖细胞的最佳扩展以用于医学应用。我们有新的证据表明，我们发现的一种特定的转录因子可能在造血过程中特定阶段的祖/后代决定中起关键作用，并希望确定它是如何实现这一目标的。

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.