Bipotential lineage determination by EKLF

描述(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来自共同的祖细胞。虽然一些转录调控因子在这一过程中很重要，但它们并不能解释双电位的结果。我们最近通过获得和丧失功能的研究、表达谱和分子分析表明，EKLF是一种转录因子，其在红系基因调控中的作用已经得到了很好的证实，在红细胞室建立之前，EKLF在红系和巨核细胞谱系的决定中发挥了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)检测EKLF的获得和功能丧失对巨核细胞-红系祖细胞做出的双潜能谱系决策的影响；(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。公共卫生相关性这些研究与描述在哺乳动物造血过程中调节双潜能决定的细胞内机制有关，并导致对特定血统的承诺。因此，它们与依赖于在医疗应用中使用祖细胞的最佳扩增的临床研究相关。我们有新的证据表明，我们确定的一个特定的转录因子在造血的特定阶段可能在祖细胞/后代决定中发挥关键作用，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.