A Single TCF Transcription Factor, Regardless of Its Activation Capacity, Is Sufficient for Effective Trilineage Differentiation of ESCs

Publication date: 5 September 2017
Source:Cell Reports, Volume 20, Issue 10
Author(s): Steven Moreira, Enio Polena, Victor Gordon, Solen Abdulla, Sujeivan Mahendram, Jiayi Cao, Alexandre Blais, Geoffrey A. Wood, Anna Dvorkin-Gheva, Bradley W. Doble
Co-expression and cross-regulation of the four TCF/LEFs render their redundant and unique functions ambiguous. Here, we describe quadruple-knockout (QKO) mouse ESCs lacking all full-length TCF/LEFs and cell lines rescued with TCF7 or TCF7L1. QKO cells self-renew, despite gene expression patterns that differ significantly from WT, and display delayed, neurectoderm-biased, embryoid body (EB) differentiation. QKO EBs have no contracting cardiomyocytes and differentiate poorly into mesendoderm but readily generate neuronal cells. QKO cells and TCF7L1-rescued cells cannot efficiently activate TCF reporters, whereas TCF7-rescued cells exhibit significant reporter responsiveness. Surprisingly, despite dramatically different transactivation capacities, re-expression of TCF7L1 or TCF7 in QKO cells restores their tri-lineage differentiation ability, with similar lineage marker expression patterns and beating cardiomyocyte frequencies observed in EBs. Both factors also similarly affect the transcriptome of QKO cells. Our data reveal that a single TCF, regardless of its activation capacity, is sufficient for effective trilineage differentiation of ESCs.

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Teaser

Moreira et al. describe the generation and characterization of mouse ESCs lacking all four full-length TCF/LEF factors. By knocking in single epitope-tagged TCF/LEFs, they reveal redundancies in the abilities of "activating" and "repressive" TCFs to rescue the differentiation deficits of the quadruple-knockout cells.


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