Control of HSC proliferation and migration by the transcription factor EGR1

描述(申请人提供)：Egr1(早期生长反应1)是即刻早期基因家族中众所周知的转录因子。我的实验室最近发现了Egr1在调节造血性造血干细胞(HSC)活性方面的一个意想不到的有趣作用。特别是，我们广泛的初步数据表明，Egr1通常既可以限制HSC的增殖，又可以促进HSC在BM利基中的保留。这些发现之所以意义重大，有几个原因。首先，Egr1代表了为数不多的已知的HSC静止调节因子之一，HSC静止对于维持HSC的功能至关重要。此外，Egr1代表了第一个被发现的HSC迁移的转录调控因子，这表明靶向该因子可能为临床移植提供诱导干细胞动员的新途径。最后，也是最值得注意的是，这个单一基因在决定HSC的增殖和解剖定位方面的作用揭示了一种新的、潜在的广泛作用机制，用于控制干细胞数量，从而在分子上协调干细胞分裂与保留在利基中。因此，Egr1-/-小鼠为发现HSC的基本特性及其临床应用提供了一个新的和重要的洞察力。通过两个集中的和互补的特定目标，本申请中提出的工作将：(1)通过功能分析确定干细胞调节因子Bmi1是否代表一个关键靶基因，负责Egr1介导的HSC增殖和定位效应；(2)识别并从功能上验证Egr1调节HSC活性的其他新靶点；以及(3)阐明Egr1-/-小鼠自发动员LT-HSC的细胞机制(S)。因此，这些研究利用Egr1和Egr1-/-小鼠作为独特的模型系统来回答长期以来关于HSC功能的分子和细胞调控的问题。与公共卫生相关：Egr1是第一个已知的HSC迁移和增殖的转录调控因子。因此，识别活跃在HSC中的Egr1调节的通路对于从机制上理解这些过程及其在干细胞功能中的作用至关重要。这些发现将对理解造血过程中HSC活性的正常、稳态控制和临床操作干细胞活性、提高HSC动员供者细胞的效率和加快移植后的造血细胞植入都具有重要意义。

DESCRIPTION (provided by applicant): EGR1 (Early Growth Response 1) is a well-known transcription factor of the immediate early gene family. My lab recently discovered an unexpected and intriguing role for EGR1 in regulating the activity of blood- forming hematopoietic stem cells (HSC). In particular, our extensive Preliminary Data demonstrate that EGR1 normally functions both to limit HSC proliferation and to promote HSC retention in the BM niche. These findings are significant for several reasons. First, EGR1 represents one of only a few known regulators of HSC quiescence, which is critical in preserving HSC function. Moreover, EGR1 represents the first identified transcriptional regulator of HSC migration, suggesting that targeting this factor may provide novel avenues to inducing stem cell mobilization for clinical transplant. Finally, and most remarkably, the role of this single gene in determining both the proliferation and anatomical localization of HSC reveals a novel and potentially broadly acting mechanism for controlling stem cell number whereby stem cell division is molecularly coordinated with retention in the niche. Egr1-/- mice thus present an extraordinary opportunity for discovering new and important insights into the fundamental properties of HSC and their clinical applications. Through two focused and complementary Specific Aims, the work proposed in this application will (1) determine by functional analyses whether the stem cell regulatory factor Bmi1 represents a key target gene responsible for EGR1-mediated effects on HSC proliferation and localization, (2) identify and functionally validate additional, novel targets of EGR1 that regulate HSC activity, and (3) elucidate the cellular mechanism(s) underlying the spontaneous mobilization of LT-HSC in Egr1-/- mice. These studies thus take advantage of EGR1 and Egr1-/- mice as unique model system to answer long-standing questions about the molecular and cellular regulation of HSC function. PUBLIC HEALTH RELEVANCE: Egr1 represents the first known transcriptional regulator of both HSC migration and proliferation. Thus, identification of the Egr1-regulated pathways active in HSC will be vital for developing a mechanistic understanding of these processes and their role in stem cell function. These findings will have significant implications both for understanding the normal, homeostatic control of HSC activity in blood formation and for manipulating stem cell activity clinically to improve the efficiency of HSC mobilization for donor cell harvest and to speed hematopoietic engraftment following transplantation.