Epigenetic Control of Nephron Progenitor Cell Lifespan

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A significant barrier to progress in the renal regeneration field is insufficient knowledge surrounding the mechanisms driving cessation of nephrogenesis. Recent genetic and epigenetic evidence demonstrated that the lifespan of nephron progenitor cells (NPCs) is not fixed. Our published and preliminary data indicate that the perinatal period in mice is characterized by remarkable changes in the single-cell chromatin landscape that tip the balance of NPC self-renewal and differentiation. The principal aim of this one-year Bridge R56 grant proposal is to generate the preliminary data requested by the Review Panel supporting our hypothesis that chromatin/histone bivalency, established through the balance of histone H3K27 methylation/demethylation, maintains the NPC lifespan by restraining chromatin accessibility to pro-differentiation transcription factors. In Aim 1A, we will generate NPC-specific Kdm6bnull mice to test the hypothesis that inhibiting H3K27 demethylation of developmental enhancers will delay the timing of cessation of nephrogenesis and enhance nephron endowment. Aim 1B will generate NPC-specific activating transcription factor (ATF4)-transgenic mice to test the hypothesis that ATF4 is sufficient to drive the cessation of nephrogenesis. We discovered differential enrichment of ATF4 motif activity in perinatal NPCs by single-cell analysis. Interestingly, ATF4 motifs are enriched in bivalent promoters, supporting the overall premise that chromatin bivalency controls NPC lifespan. Collectively, the results of these studies will form a strong basis for the competitive renewal application, which will delve into the chromatin-based mechanisms of cessation of nephrogenesis. Successful completion of this project will have broad impacts on defining the rules of epigenetic control of nephron progenitor maintenance. This knowledge may be translated to optimizing nephron regeneration and understanding epigenetic programming of renal disease.