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.
s: Congenital kidney diseases, including renal agenesis and hypodysplasia, are the most common types of birth defects. This grant proposes to elucidate genetic bases of these congenital diseases and address several key questions of when and how transcription factors interact with chromatin remodeling complexes to mediate a small group of progenitor cells to generate large numbers of individual nephrons (blood-filtering units) in a mature kidney. Understanding how nephron progenitors are specified and maintained may eventually lead to prevention or repair of such renal diseases.
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