GATA3 regulation in transcriptional networks during hematopoietic cell developmen

描述(由申请人提供)：胸腺中T淋巴细胞的成熟是由造血祖细胞的持续涌入维持的，造血祖细胞最终来自骨髓造血干细胞。转录因子GATA-3是T细胞和胸腺自然杀伤(NK)细胞发育的关键调节因子，已被证明在T细胞发育的多个阶段都是至关重要的。我们最近的研究表明，GATA-3是胸腺中最不成熟的T细胞，是最早的T细胞前体细胞(ETP)的发育所必需的。作为对比，我们还证明了GATA-3在ETP阶段之前对于具有T细胞潜能的胎肝或成人骨髓前胸腺前体细胞的发育不是必需的。这一重要的证明在功能上很难解决，因为没有T细胞可以从GATA3缺失的祖细胞中产生，但我们能够使用一种新的GATA3-EGFP亚型等位基因明确地证明这一要求。因此，GATA-3在T淋巴细胞生成的最早阶段以及胸腺细胞发育的中后期和外周的CD4+T细胞Th2分化中都是必需的。尽管GATA-3(转录因子)和GATA3(基因)介导的转录分级在外周T细胞中已经开始被表征，但它在胸腺T细胞转录调控网络中的分级活性仍然很大程度上是未知的。我们最近发现了一个位于GATA3结构基因3‘端的GATA3T和NK细胞特异性增强子。在这里，我们建议描述以GATA-3为中心的转录网络的特征，该网络控制T细胞从最不成熟的造血祖细胞阶段到成熟的Th2阶段的发育。有助于我们理解GATA-3在胸腺生成早期的调节可能对于最终破译T细胞白血病和淋巴瘤的病因和进展至关重要，因为GATA-3的异常表达被认为是这些疾病的一个亚组的病因。

DESCRIPTION (provided by applicant): T lymphocyte maturation in the thymus is maintained by the continuous influx of hematopoietic progenitors that are ultimately derived from bone marrow hematopoietic stem cells. Transcription factor GATA-3 is a critical regulator of T cell and thymic natural killer (NK) cell development, and has been shown to be vital for multiple stages of T cell development. Our recent studies revealed that GATA-3 is required for the development of the earliest T cell progenitor (ETP), the most immature T cell in the thymus. By way of contrast, we also demonstrated that GATA-3 is not required prior to the ETP stage for the development of fetal liver or adult bone marrow pre-thymic progenitors that bear T cell potential. This vital demonstration was functionally difficult to address because no T cells can be generated from GATA3-null progenitors, but we were able to definitively demonstrate this requirement using a novel Gata3-eGFP hypomorphic allele. Thus GATA-3 is required at the earliest stage of T lymphopoiesis as well as at intermediate and late stages of thymocyte development and for CD4+ T cell Th2 differentiation in the periphery. Although the transcriptional hierarchy mediated by GATA-3 (the transcription factor) and through Gata3 (the gene) is beginning to be characterized in peripheral T cells, its hierarchical activity in the T cell transcriptional regulaory network in the thymus remains largely unknown. We recently identified a Gata3 T and NK cell-specific enhancer located 280 kbp 3' to the Gata3 structural gene. Here we propose to characterize the GATA-3-centric transcriptional network that controls T cell development from the most immature hematopoietic progenitor stages through to the mature Th2 stage. Contributing to our understanding of GATA-3 regulation in early thymopoiesis may be critical for eventually deciphering the etiology and progression of T cell leukemias and lymphomas, since aberrant GATA- 3 expression has been implicated as a causal agent in a subset of these diseases.