Elsevier

Developmental Biology

Volume 362, Issue 1, 1 February 2012, Pages 94-103
Developmental Biology

EVEN-SKIPPED HOMEOBOX 1 controls human ES cell differentiation by directly repressing GOOSECOID expression

https://doi.org/10.1016/j.ydbio.2011.11.017Get rights and content
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Abstract

TGFß signaling patterns the primitive streak, yet little is known about transcriptional effectors that mediate the cell fate choices during streak-like development in mammalian embryos and in embryonic stem (ES) cells. Here we demonstrate that cross-antagonistic actions of EVEN-SKIPPED HOMEOBOX 1 (EVX1) and GOOSECOID (GSC) regulate cell fate decisions in streak-like progenitors derived from human ES cells exposed to BMP4 and/or activin. We found that EVX1 repressed GSC expression and promoted formation of posterior streak-like progeny in response to BMP4, and conversely that GSC repressed EVX1 expression and was required for development of anterior streak-like progeny in response to activin. Chromatin immunoprecipitation assays showed that EVX1 bound to the GSC 5′-flanking region in BMP4 treated human ES cells, and band shift assays identified two EVX1 binding sites in the GSC 5′-region. Significantly, we found that intact EVX1 binding sites were required for BMP4-mediated repression of GSC reporter constructs. We conclude that BMP4-induced EVX1 repress GSC directly and the two genes form the core of a gene regulatory network (GRN) controlling cell fates in streak-like human ES cell progeny.

Highlights

► EVX1 repress GSC and promotes formation of posterior streak-like cells in response to BMP4. ► GSC repress EVX1 and promotes formation of anterior streak-like cells in response to activin. ► EVX1 repress GSC directly via two functional EVX1 binding sites in the GSC 5′-region. ► EVX1 and GSC forms the core of a GRN controlling cell fates in streak-like ES cell progeny.

Keywords

EVX1
GSC
Brachyury
TGFbeta
Human ES cells

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