Transcription factors in early kidney development

我们的目标是阐明Eya 1及其辅因子在肾单位祖细胞中调控的遗传网络 命运特化、增殖和分化。Eya 1是一种转录辅激活因子， 通过与DNA结合蛋白的相互作用进行转录。我们已经证明Eya 1形成了一个密钥， 转录复合物：（1）同源结构域转录因子Six家族成员Six 1/4指定 后肾间充质（MM），和（2）Six 2和Myc在肾单位祖细胞中维持和 更新祖先。通过质谱分析，我们已经确定了 SWI/SNF染色质重塑复合物作为Eya 1的相互作用蛋白。虽然染色质重塑是 已知通过改变染色质结构和促进必需的 由于Eya 1是转录所需的因子，目前尚不清楚SWI/SNF复合物是否与Eya 1相互作用， 以及其他因素赋予特定的转录程序，确保MM规范， 肾单位形成。本申请提出采用遗传的、基因组的、分子的和转基因的方法， 系统检验Eya 1与SWI/SNF染色质相互作用的假设的方法 重塑复合物和其他伙伴转录因子，以创建激活 基因转录指定肾单位的命运，决定肾单位祖细胞自我更新或经历 分化，并确定肾单位节段身份。具体地说，我们将描述基因 Eya 1和Brg 1在MM祖细胞发育不同阶段调控的网络。本研究 将提供Eya 1-Brg 1与其在Eya 1表达细胞中的靶点在不同温度下的关联的广泛视图。 在肾单位形成过程中的阶段，并为未来发现顺式调节模块提供了丰富的来源- 相关机制。这些信息可用于指导肾单位的修复和再生。本研究 将为先天性肾单位缺陷的遗传网络提供有价值的见解。

Our goal is to elucidate the genetic networks controlled by Eya1 and its cofactors in nephron progenitor cell fate specification, proliferation and differentiation. Eya1 is a transcriptional coactivator that indirectly affects transcription through interaction with DNA-binding proteins. We have shown that Eya1 forms a key transcriptional complex with: (1) the homeodomain transcription factor Six family members Six1/4 to specify the metanephric mesenchyme (MM), and (2) Six2 and Myc in the nephron progenitors to maintain and renew the progenitors. Through mass spectrometry analysis, we have identified the components of the SWI/SNF chromatin remodeling complex as Eya1's interacting proteins. While chromatin remodelers are known to regulate gene expression by altering chromatin structure and facilitating recruitment of essential factors required for transcription, it remains unclear whether the SWI/SNF complex interact with Eya1 as well as other factors to confer specific transcriptional programs that ensure the MM specification and nephron formation. This application proposes to take genetic, genomic, molecular and transgenic approaches to systematically test the hypothesis that Eya1 interacts with the SWI/SNF chromatin remodeling complex and other partner transcription factors to create a combinatorial code that activates gene transcription to specify a nephron fate, dictate the nephron progenitors to either self-renew or undergo differentiation, and determine nephron segmental identity. Specifically, we will characterize the genetic networks controlled by Eya1 and Brg1 in the MM progenitor cell development at different stages. This study will provide a broad view of Eya1-Brg1 association with their targets in Eya1-expressing cells at different stages during nephron formation and provide a rich source for future discovery of cis-regulatory module- associated mechanisms. The information can be used to guide nephron repair and regeneration. This study will provide valuable insights into the genetic networks that underlie congenital nephron deficits.