A β-catenin-driven switch in TCF/LEF transcription factor binding to DNA target sites promotes commitment of mammalian nephron progenitor cells.
Qiuyu GuoAlbert KimBin LiAndrew RansickHelena BugacovXi ChenNils LindströmAaron BrownLeif OxburghBing RenAndrew P McMahonPublished in: eLife (2021)
The canonical Wnt pathway transcriptional co-activator β-catenin regulates self-renewal and differentiation of mammalian nephron progenitor cells (NPCs). We modulated β-catenin levels in NPC cultures using the GSK3 inhibitor CHIR99021 (CHIR) to examine opposing developmental actions of β-catenin. Low CHIR-mediated maintenance and expansion of NPCs are independent of direct engagement of TCF/LEF/β-catenin transcriptional complexes at low CHIR-dependent cell-cycle targets. In contrast, in high CHIR, TCF7/LEF1/β-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, β-catenin's direct transcriptional role is restricted to the induction of NPCs, where rising β-catenin levels switch inhibitory TCF7L1/TCF7L2 complexes to activating LEF1/TCF7 complexes at primed gene targets poised for rapid initiation of a nephrogenic program.
Keyphrases
- cell proliferation
- transcription factor
- epithelial mesenchymal transition
- cell cycle
- gene expression
- stem cells
- signaling pathway
- genome wide identification
- genome wide
- dna methylation
- pi k akt
- dna binding
- oxidative stress
- immune response
- computed tomography
- quality improvement
- inflammatory response
- single molecule
- cell free
- quantum dots
- nucleic acid
- copy number
- circulating tumor
- genome wide analysis