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Genome-wide map of open chromatin in mouse nephron progenitor cells

ABSTRACT: During embryonic kidney development, nephron progenitor cells (NPCs) self-renew and differentiate into all cells in mature nephrons. The Wnt signaling components Wnt9b and β-catenin are required for both NPC self-renewal and differentiation. A low level of Wnt/β-catenin are associated with NPC self-renewal while a high level with differentiation. To investigate the transcriptional mechanisms behind Wnt/β-catenin-driven regulation of NPCs states, we modeled NPC self-renewal and differentiation in vitro with NPEM (Brown et al., 2015) supplemented with low (1.25 μM) or high (5 μM) concentration of CHIR22091 (CHIR), a small molecule GSK3β inhibitor that stabilizes β-catenin. To investigate change of NPC chromatin landscape under influence of CHIR treatment, here we generated ATAC-Seq data from primary NPC, as well as NPC cultured in low and high CHIR concentration.

ORGANISM(S): Mus musculus

PROVIDER: GSE131116 | GEO | 2021/01/07

REPOSITORIES: GEO

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Project description:Wnt/β-catenin signaling is a highly conserved molecular pathway that plays a crucial role in stem/progenitor systems and cancer. β-catenin, the main Wnt pathway effector, has two pools within a cell: one for cell-cell adhesion at the membrane and the other for transcriptional functions in the nucleus. However, the mechanism by which β-catenin mediates both roles remain unclear. The tightly controlled, well characterized system of nephrogenesis is an ideal model to decouple the roles of β-catenin at the membrane and in the nucleus. In kidney development, a delicate balance of nephron progenitor cell self-renewal and differentiation is required for the mesenchymal to epithelial transition (MET) in nephrogenesis and is driven by Wnt/β-catenin signaling. Given an ability to isolate and manipulate large numbers of NPCs in tissue culture, we can dissect the dual nature of β-catenin as a transcriptional activator and component of a cell membrane complex in adhesion. We pioneered a method using CRISPR/Cas9 gene editing to rapidly remove β-catenin, Tcf/Lef factors and simultaneous cadherin genes in primary NPCs. We have characterized the effects of modulating β-catenin and integrated RNA-seq results from β-catenin’s removal with mouse ChIP-seq and mouse single cell RNA -seq data. Functional analysis of β-catenin removal provides strong evidence for β-catenin regulation of NPC proliferation, independent of a direct Lef/Tcf associated transcriptional program. Together these data suggest β-catenin mediates aggregation, the first step in MET, through β-catenin mediated cell adhesion complexes while simultaneous transcriptional activation within these structures initiates the nephrogenic program. The studies provide new insight into the direct transcriptional role of Lef/Tcf/β-catenin complexes associated with the initiation of a nephron forming program. Overall, this study enhances an understanding of the molecular mechanisms underlying kidney development and the dual nature of β-catenin stem/progenitor systems at large.

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Genome-wide map of open chromatin in mouse nephron progenitor cells

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