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

TY - JOUR

T1 - EVEN-SKIPPED HOMEOBOX 1 controls human ES cell differentiation by directly repressing GOOSECOID expression

AU - Kalisz, Mark

AU - Winzi, Maria Karin

AU - Bisgaard, Hanne Cathrine

AU - Serup, Palle

N1 - Copyright © 2011 Elsevier Inc. All rights reserved.

PY - 2012/2/1

Y1 - 2012/2/1

N2 - 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.

AB - 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.

U2 - 10.1016/j.ydbio.2011.11.017

DO - 10.1016/j.ydbio.2011.11.017

M3 - Journal article

C2 - 22178155

SN - 0012-1606

VL - 362

SP - 94

EP - 103

JO - Developmental Biology

JF - Developmental Biology

IS - 1

ER -