A β-catenin-driven switch in TCF/LEF transcription factor binding to DNA target sites promotes commitment of mammalian nephron progenitor cells

The canonical Wnt pathway transcriptional co-activator beta-catenin regulates self-renewal and differentiation of mammalian nephron progenitor cells (NPCs). We modulated beta-catenin levels in NPC cultures using the GSK3 inhibitor CHIR99021 (CHIR) to examine opposing developmental actions of beta-catenin. Low CHIR-mediated maintenance and expansion of NPCs are independent of direct engagement of TCF/LEF/beta-catenin transcriptional complexes at low CHIR-dependent cell-cycle targets. In contrast, in high CHIR, TCF7/LEF1/beta-catenin complexes replaced TCF7L1/TCF7L2 binding on enhancers of differentiation-promoting target genes. Chromosome confirmation studies showed pre-established promoter-enhancer connections to these target genes in NPCs. High CHIR-associated de novo looping was observed in positive transcriptional feedback regulation to the canonical Wnt pathway. Thus, beta-catenin's direct transcriptional role is restricted to the induction of NPCs, where rising beta-catenin levels switch inhibitory TCF7L1/TCF7L2 complexes to activating LEF1/TCF7 complexes at primed gene targets poised for rapid initiation of a nephrogenic program.

Automated summary

The study reveals that beta-catenin plays a crucial role in regulating self-renewal and differentiation of mammalian nephron progenitor cells. The modulation of beta-catenin levels using the GSK3 inhibitor CHIR showed opposing effects on NPC development, with low CHIR promoting maintenance and expansion while high CHIR inducing differentiation. Additionally, the study found that in high CHIR conditions, beta-catenin interacts with TCF7/LEF1 complexes to activate enhancers of differentiation-promoting target genes.