Transcription factors in early kidney development

我们的目标是阐明Eya1及其辅助因子在肾单位祖细胞中控制的遗传网络。 命运指定、增殖和分化。EYA1是一种转录辅助激活因子，间接影响 通过与DNA结合蛋白相互作用进行转录。我们已经证明了Eya1形成了一个密钥 转录复合体具有：(1)同源结构域转录因子6个家族成员SIX1/4来指定 后肾间充质(MM)，以及(2)SIX2和Myc在肾单位祖细胞中的维持和 更新祖先。通过质谱分析，我们鉴定了黄连的成分。 Swi/Snf染色质重塑复合体作为EYA1‘S相互作用蛋白。而染色质重构体是 已知通过改变染色质结构和促进必要的招募来调节基因表达 转录所需的因子，目前尚不清楚SWI/SNF复合体是否与Eya1作为 以及其他因素，以授予特定的转录程序，以确保MM规范和 肾单位形成。这一应用提出了将遗传、基因组、分子和转基因 系统检验Eya1与SWI/SNF染色质相互作用假说的方法 重塑复合体和其他伙伴转录因子，以创建激活的组合密码 基因转录来指定肾单位的命运，决定肾单位祖细胞要么自我更新，要么经历 分化，并确定肾单位节段的身份。具体地说，我们将描述基因 在MM祖细胞发育的不同阶段，Eya1和BRG1调控的网络。本研究 将提供Eya1-BRG1与其靶标在不同表达Eya1的细胞中的关联的广泛视角 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背后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.