GATA3 regulation in transcriptional networks during hematopoietic cell developmen

描述（由申请人提供）：胸腺中的T淋巴细胞成熟是由最终来源于骨髓造血干细胞的造血祖细胞的持续流入维持的。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，已被证明对T细胞发育的多个阶段至关重要。我们最近的研究表明，GATA-3是胸腺中最不成熟的T细胞——最早的T细胞祖细胞（ETP）发育所必需的。通过对比，我们也证明了GATA-3在具有T细胞潜能的胎儿肝脏或成人骨髓胸腺前祖细胞的发育中在ETP阶段之前并不需要。这个重要的证明在功能上很难解决，因为没有T细胞可以从GATA3-null祖细胞中产生，但是我们能够使用一个新的Gata3-eGFP亚形态等位基因明确地证明这一要求。因此，GATA-3在T淋巴形成的早期、胸腺细胞发育的中后期以及外周血CD4+ T细胞Th2分化中都是必需的。尽管由GATA-3（转录因子）和通过GATA-3（基因）介导的转录层次结构开始在外周T细胞中被表征，但其在胸腺T细胞转录调控网络中的层次活性在很大程度上仍然未知。我们最近发现了一个位于Gata3结构基因280 kbp 3'的Gata3 T和NK细胞特异性增强子。在这里，我们提出表征以gata -3为中心的转录网络，该网络控制T细胞从最不成熟的造血祖细胞阶段发育到成熟的Th2阶段。帮助我们理解早期胸腺发育中GATA-3的调控可能对最终解读T细胞白血病和淋巴瘤的病因和进展至关重要，因为异常的GATA-3表达已被认为是这些疾病的一个子集的致病因子。

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. PUBLIC HEALTH RELEVANCE: T lymphocytes are an indispensable component of the vertebrate adaptive immune response, and defects or aberrant development during T lymphopoiesis can result in compromised immunological competence or leukemia. The interplay of multiple transcription factors regulates proper T lymphocyte development, and GATA-3 plays a critical role in their maturation and activation. Successful execution of this research program will fundamentally contribute to our understanding of the transcriptional network(s) that controls T cell development from hematopoietic stem cells, which in turn should contribute in the future to the development of new therapeutic approaches to hematopoietic diseases, including leukemia.