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Genome-wide map of Tcf/Lef transcription factors, β-catenin, Six2 and chromatin marks 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. We have found the Tcf/Lef family repressors Tcf7l1 and Tcf7l2 are enriched in low CHIR condition, while the activators Tcf7 and Lef1 in high CHIR condition, correlating with the NPC differentiation program transiting from being repressed to activated. To identify direct transcriptional targets of Tcf/Lef factors and β-catenin, here we generated ChIP-Seq data from primary NPC, as well as NPC cultured in low and high CHIR concentration.

ORGANISM(S): Mus musculus

PROVIDER: GSE131117 | 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 Tcf/Lef transcription factors, β-catenin, Six2 and chromatin marks in mouse nephron progenitor cells

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