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Chromatin and gene-regulatory dynamics of mouse nephron progenitors at single-cell resolution [Single cell Multiome ATAC + Gene Expression]

ABSTRACT: Background: Unraveling the dynamic accessibility of regulatory chromatin at single-cell resolution is key to understanding stem/progenitor cell fate choices in health and disease. Nephron progenitor cells (NPCs) are a multipotent population giving rise to all cell types of the nephron, from the glomerular epithelium to the distal tubule. At any given time, the NPC’s choice to self-renew or differentiate and gain a new identity is determined not only by its transcription factor repertoire but also by the genome accessibility of the cognate cis-regulatory elements. Methods: We performed singleome and multiome analysis of chromatin accessibility and gene expression in thousands of embryonic and neonatal NPCs toward defining the regulatory landscape driving fate choices during nephrogenesis. Results: We show that chromatin accessibility recovers the diverse states of NPCs and precursor states of proximal and distal nephron epithelial cells. We define the key cell type-specific transcriptional regulators across pseudotime and NPC age. We find that chromatin accessibility in the podocyte lineage is established early in the trajectory and identify a subset of Forkhead factors exhibiting high chromatin activity in podocyte precursors. We also determined that strong linkages between cis-regulatory elements and expression levels distinguish fate-determining TFs. Conclusions: Single-cell mapping of accessible and active chromatin defines the regulatory landscape of nephrogenesis and provides a foundation for future studies in disease states characterized by abnormal nephrogenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE180900 | GEO | 2022/04/01

REPOSITORIES: GEO

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Project description:Bulk ATAC_seq on GFP expressing FACS-isolated cells from E16.5 and P0 Six2TGC and compound Ezh1 and Ezh2 mutant kidneys( Six2TGC_Ezh2-/- , Ezh1+/-; Six2TGC_Ezh2-/-; and Ezh1-/- ; scRNA-seq analysis of NPCs (Six2/GFP+ cells) from E16.5 as well as P2 kidneys. Genotypes analyzed: Six2TGC (E16.5&P2), Six2TGCEzh2-/- (E16.5), Ezh1+/-;Six2TGCEzh2-/- (E16.5), and Ezh2-/-;Six2TGCEzh2-/- (E16.5) Six2/GFP+ nephron progenitor cells (NPCs) give rise to all epithelial cell types of the nephron, the filtering unit of the kidney. NPCs have a limited lifespan and are consumed near the time of birth. Pre-term birth or prenatal stress further shorten the lifespan of NPCs and result in nephron deficit and chronic kidney disease. Accordingly, there is a pressing need to better understand the factors that regulate NPC lifespan in order to develop novel regenerative strategies. Epigenetic factors are implicated in maintenance of organ-restricted progenitors such as NPCs, but the chromatin-based mechanisms are not well understood. In this study, we examined the role of the H3K27 methyltransferases, Enhancer of zeste (Ezh1 and Ezh2), in NPC maintenance using a combination of gene targeting, chromatin profiling, and single-cell RNA analysis. We find that Ezh2 expression correlates with NPC growth potential, and that Ezh2 is the dominant H3K27 methyltransferase in NPCs and epithelial descendants. Surprisingly, NPCs lacking H3K27me3 maintain their progenitor state albeit cycle slowly leading to formation of fewer nephrons. Unlike Ezh2 loss-of-function, dual inactivation of Ezh1 and Ezh2 triggers overexpression of the transcriptional repressor Hey1 and downregulation of Six2 and result in unscheduled activation of Wnt4-driven differentiation, early termination of nephrogenesis and severe renal dysgenesis. Double-mutant NPCs also overexpress the Six family member, Six1. However, in this context, Six1 is unable to access the closed Six2 enhancer and fails to maintain NPC stemness. At the chromatin level, Ezh1 and Ezh2 act by restricting accessibility of AP1 factors to their genomic binding motifs and their absence provokes a regulatory landscape akin of differentiated and non-lineage cells. We conclude that Ezh2 is required for NPC renewal potential, while maintenance of NPC lifespan and tempering the differentiation program require cooperation of both Ezh1 and Ezh2.

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Chromatin and gene-regulatory dynamics of mouse nephron progenitors at single-cell resolution [Single cell Multiome ATAC + Gene Expression]

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