Unknown

Dataset Information

0

Convergence of cMyc and β-catenin on Tcf7l1 enables endoderm specification.


ABSTRACT: The molecular machinery that directs formation of definitive endoderm from pluripotent stem cells is not well understood. Wnt/β-catenin and Nodal signalling have been implicated, but the requirements for lineage specification remain incompletely defined. Here, we demonstrate a potent effect of inhibiting glycogen synthase kinase 3 (GSK3) on definitive endoderm production. We find that downstream of GSK3 inhibition, elevated cMyc and β-catenin act in parallel to reduce transcription and DNA binding, respectively, of the transcriptional repressor Tcf7l1. Tcf7l1 represses FoxA2, a pioneer factor for endoderm specification. Deletion of Tcf7l1 is sufficient to allow upregulation of FoxA2 in the presence of Activin. In wild-type cells, cMyc contributes by reducing Tcf7l1 mRNA, while β-catenin acts on Tcf7l1 protein. GSK3 inhibition is further required for consolidation of endodermal fate via upregulation of Sox17, highlighting sequential roles for Wnt signalling. The identification of a cMyc/β-catenin-Tcf7l1-FoxA2 axis reveals a de-repression mechanism underlying endoderm induction that may be recapitulated in other developmental and patho-logical contexts.

SUBMITTER: Morrison G 

PROVIDER: S-EPMC4741304 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

altmetric image

Publications

Convergence of cMyc and β-catenin on Tcf7l1 enables endoderm specification.

Morrison Gillian G   Scognamiglio Roberta R   Trumpp Andreas A   Smith Austin A  

The EMBO journal 20151216 3


The molecular machinery that directs formation of definitive endoderm from pluripotent stem cells is not well understood. Wnt/β-catenin and Nodal signalling have been implicated, but the requirements for lineage specification remain incompletely defined. Here, we demonstrate a potent effect of inhibiting glycogen synthase kinase 3 (GSK3) on definitive endoderm production. We find that downstream of GSK3 inhibition, elevated cMyc and β-catenin act in parallel to reduce transcription and DNA bindi  ...[more]

Similar Datasets

| S-EPMC3265065 | biostudies-literature
| S-EPMC5438253 | biostudies-literature
| S-EPMC4996431 | biostudies-literature
| S-EPMC3759994 | biostudies-literature
| S-EPMC5868997 | biostudies-literature
| S-EPMC10643375 | biostudies-literature
| S-EPMC3621485 | biostudies-literature
| S-EPMC3707317 | biostudies-literature
| S-EPMC11903683 | biostudies-literature
| S-EPMC9169638 | biostudies-literature