Regulators of the Erythroid Terminal Differentiation Decision and their Connection to the Cell Cycle

 描述(申请人提供)：BFUe是最原始的定向红系祖细胞，能够广泛增殖。BFUe分化为CFUe，这是一种增殖能力非常有限的细胞。PU.1是BFUe自我更新所必需的一种造血调控转录因子(Tf)。PU1抑制BFUe分化。PU.1表达下调是BFUe分化为CFUe所必需的。尽管PU1‘S在调控末端分化决策中起着中心作用，但控制PU1’S表达和下调的分子机制尚不清楚。我们建议找出控制BFUe中PU.1表达的顺式调控元件，并在这些前体细胞进入末端分化时下调PU.1的表达。利用基因表达的计算分析、芯片序列和其他类型的全基因组数据集，我们已经确定了几个DNA结合蛋白作为控制BFUe中PU.1表达的候选蛋白，包括SATB1、E2F4、RUNX和JUN。分析还表明，其中一些因子RUNX和JUN与PU1协同调节一大组促进BFUe增殖并拮抗其末端分化的基因。我们建议确定这些因素是否调节PU1的表达。我们还建议确定它们是否与PU.1协同工作，以控制红系细胞中的一组重要基因靶点。这项工作的成功完成将为调节红细胞输出的转录网络提供重要的见解。

 DESCRIPTION (provided by applicant): BFUe, the most primitive committed erythroid progenitors, are capable of extensive proliferation. BFUe differentiate into CFUe, cells with very restricted proliferative potential. Pu.1 is a hematopoietic, master regulatory ETS transcription factor (TF) that is required for BFUe self-renewal. PU.1 inhibits BFUe differentiation. Down regulation of PU.1 occurs and is required for BFUe to differentiate into CFUe. Despite Pu.1's central role in regulating the terminal differentiation decision, the molecular mechanism controlling Pu.1's expression and down-regulation are not known. We propose to identify the cis-regulatory elements that control Pu.1 expression in BFUe and it's down regulation as these progenitors enter terminal differentiation. Using computational analysis of gene expression, ChIP Seq and other types of genome-wide data sets, we have identified several DNA binding proteins as candidates for controlling Pu.1 expression in BFUe, including SATB1, E2F4, Runx and Jun. The analysis also suggests that some of these factors, Runx and Jun, collaborate with Pu.1 to regulate a large set of genes that promote proliferation of BFUe and antagonize their terminal differentiation. We propose to determine whether these factors regulate Pu.1 expression. We also propose to determine whether they work in concert with Pu.1 to control a set of important gene targets in erythroid cells. The successful completion of this work will provide essential insights into the transcriptional networks that regulate red blood cell output.