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bioRxiv · 10.1101/2020.10.26.356410

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

Guo, Q.·Kim, A. D.·Li, B.·Ransick, A.·Bugacov, H.·Chen, X.·Lindstrom, N. O.·Brown, A.·Oxburgh, L.·Ren, B.·McMahon, A. P.
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Abstract

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 CHIR9902 (CHIR) to examine opposing developmental actions of {beta}-catenin. Low CHIR-mediated maintenance and expansion of NPCs is 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}-catenins 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.

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Guo, Q., Kim, A. D., Li, B., Ransick, A., Bugacov, H., Chen, X., Lindstrom, N. O., Brown, A., Oxburgh, L., Ren, B., McMahon, A. P.. 2020-10-27. A β-catenin-driven switch in TCF/LEF transcription factor binding to DNA targets sites promotes commitment of mammalian nephron progenitor cells. https://doi.org/10.1101/2020.10.26.356410

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