UTX regulates mesoderm differentiation of embryonic stem cells independent of H3K27 demethylase activity

Chaochen Wang, Ji Eun Lee, Young Wook Cho, Ying Xiao, Qihuang Jin, Chengyu Liu, Kai Ge

Research output: Contribution to journalArticle

99 Citations (Scopus)

Abstract

To investigate the role of histone H3K27 demethylase UTX in embryonic stem (ES) cell differentiation, we have generated UTX knockout (KO) and enzyme-dead knock-in male ES cells. Deletion of the X-chromosome-encoded UTX gene in male ES cells markedly decreases expression of the paralogous UTY gene encoded by Y chromosome, but has no effect on global H3K27me3 level, Hox gene expression, or ES cell self-renewal. However, UTX KO cells show severe defects in mesoderm differentiation and induction of Brachyury, a transcription factor essential for mesoderm development. Surprisingly, UTX regulates mesoderm differentiation and Brachyury expression independent of its enzymatic activity. UTY, which lacks detectable demethylase activity, compensates for the loss of UTX in regulating Brachyury expression. UTX and UTY bind directly to Brachyury promoter and are required for Wnt/β-catenin signaling-induced Brachyury expression in ES cells. Interestingly, male UTX KO embryos express normal levels of UTY and survive until birth. In contrast, female UTX KO mice, which lack the UTY gene, show embryonic lethality before embryonic day 11.5. Female UTX KO embryos show severe defects in both Brachyury expression and embryonic development of mesoderm-derived posterior notochord, cardiac, and hematopoietic tissues. These results indicate that UTX controls mesoderm differentiation and Brachyury expression independent of H3K27 demethylase activity, and suggest that UTX and UTY are functionally redundant in ES cell differentiation and early embryonic development.

Original languageEnglish (US)
Pages (from-to)15324-15329
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number38
DOIs
StatePublished - Sep 18 2012

Fingerprint

Mesoderm
Embryonic Stem Cells
Embryonic Development
Cell Differentiation
Embryonic Structures
Histone Demethylases
Y-Linked Genes
Notochord
Catenins
Homeobox Genes
X Chromosome
Brachyury protein
Knockout Mice
Genes
Transcription Factors
Parturition
Gene Expression
Enzymes

ASJC Scopus subject areas

  • General

Cite this

UTX regulates mesoderm differentiation of embryonic stem cells independent of H3K27 demethylase activity. / Wang, Chaochen; Lee, Ji Eun; Cho, Young Wook; Xiao, Ying; Jin, Qihuang; Liu, Chengyu; Ge, Kai.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 38, 18.09.2012, p. 15324-15329.

Research output: Contribution to journalArticle

Wang, Chaochen ; Lee, Ji Eun ; Cho, Young Wook ; Xiao, Ying ; Jin, Qihuang ; Liu, Chengyu ; Ge, Kai. / UTX regulates mesoderm differentiation of embryonic stem cells independent of H3K27 demethylase activity. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 38. pp. 15324-15329.
@article{f1ec7ea123804d9a9e1f1bb92e68c19e,
title = "UTX regulates mesoderm differentiation of embryonic stem cells independent of H3K27 demethylase activity",
abstract = "To investigate the role of histone H3K27 demethylase UTX in embryonic stem (ES) cell differentiation, we have generated UTX knockout (KO) and enzyme-dead knock-in male ES cells. Deletion of the X-chromosome-encoded UTX gene in male ES cells markedly decreases expression of the paralogous UTY gene encoded by Y chromosome, but has no effect on global H3K27me3 level, Hox gene expression, or ES cell self-renewal. However, UTX KO cells show severe defects in mesoderm differentiation and induction of Brachyury, a transcription factor essential for mesoderm development. Surprisingly, UTX regulates mesoderm differentiation and Brachyury expression independent of its enzymatic activity. UTY, which lacks detectable demethylase activity, compensates for the loss of UTX in regulating Brachyury expression. UTX and UTY bind directly to Brachyury promoter and are required for Wnt/β-catenin signaling-induced Brachyury expression in ES cells. Interestingly, male UTX KO embryos express normal levels of UTY and survive until birth. In contrast, female UTX KO mice, which lack the UTY gene, show embryonic lethality before embryonic day 11.5. Female UTX KO embryos show severe defects in both Brachyury expression and embryonic development of mesoderm-derived posterior notochord, cardiac, and hematopoietic tissues. These results indicate that UTX controls mesoderm differentiation and Brachyury expression independent of H3K27 demethylase activity, and suggest that UTX and UTY are functionally redundant in ES cell differentiation and early embryonic development.",
author = "Chaochen Wang and Lee, {Ji Eun} and Cho, {Young Wook} and Ying Xiao and Qihuang Jin and Chengyu Liu and Kai Ge",
year = "2012",
month = "9",
day = "18",
doi = "10.1073/pnas.1204166109",
language = "English (US)",
volume = "109",
pages = "15324--15329",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "38",

}

TY - JOUR

T1 - UTX regulates mesoderm differentiation of embryonic stem cells independent of H3K27 demethylase activity

AU - Wang, Chaochen

AU - Lee, Ji Eun

AU - Cho, Young Wook

AU - Xiao, Ying

AU - Jin, Qihuang

AU - Liu, Chengyu

AU - Ge, Kai

PY - 2012/9/18

Y1 - 2012/9/18

N2 - To investigate the role of histone H3K27 demethylase UTX in embryonic stem (ES) cell differentiation, we have generated UTX knockout (KO) and enzyme-dead knock-in male ES cells. Deletion of the X-chromosome-encoded UTX gene in male ES cells markedly decreases expression of the paralogous UTY gene encoded by Y chromosome, but has no effect on global H3K27me3 level, Hox gene expression, or ES cell self-renewal. However, UTX KO cells show severe defects in mesoderm differentiation and induction of Brachyury, a transcription factor essential for mesoderm development. Surprisingly, UTX regulates mesoderm differentiation and Brachyury expression independent of its enzymatic activity. UTY, which lacks detectable demethylase activity, compensates for the loss of UTX in regulating Brachyury expression. UTX and UTY bind directly to Brachyury promoter and are required for Wnt/β-catenin signaling-induced Brachyury expression in ES cells. Interestingly, male UTX KO embryos express normal levels of UTY and survive until birth. In contrast, female UTX KO mice, which lack the UTY gene, show embryonic lethality before embryonic day 11.5. Female UTX KO embryos show severe defects in both Brachyury expression and embryonic development of mesoderm-derived posterior notochord, cardiac, and hematopoietic tissues. These results indicate that UTX controls mesoderm differentiation and Brachyury expression independent of H3K27 demethylase activity, and suggest that UTX and UTY are functionally redundant in ES cell differentiation and early embryonic development.

AB - To investigate the role of histone H3K27 demethylase UTX in embryonic stem (ES) cell differentiation, we have generated UTX knockout (KO) and enzyme-dead knock-in male ES cells. Deletion of the X-chromosome-encoded UTX gene in male ES cells markedly decreases expression of the paralogous UTY gene encoded by Y chromosome, but has no effect on global H3K27me3 level, Hox gene expression, or ES cell self-renewal. However, UTX KO cells show severe defects in mesoderm differentiation and induction of Brachyury, a transcription factor essential for mesoderm development. Surprisingly, UTX regulates mesoderm differentiation and Brachyury expression independent of its enzymatic activity. UTY, which lacks detectable demethylase activity, compensates for the loss of UTX in regulating Brachyury expression. UTX and UTY bind directly to Brachyury promoter and are required for Wnt/β-catenin signaling-induced Brachyury expression in ES cells. Interestingly, male UTX KO embryos express normal levels of UTY and survive until birth. In contrast, female UTX KO mice, which lack the UTY gene, show embryonic lethality before embryonic day 11.5. Female UTX KO embryos show severe defects in both Brachyury expression and embryonic development of mesoderm-derived posterior notochord, cardiac, and hematopoietic tissues. These results indicate that UTX controls mesoderm differentiation and Brachyury expression independent of H3K27 demethylase activity, and suggest that UTX and UTY are functionally redundant in ES cell differentiation and early embryonic development.

UR - http://www.scopus.com/inward/record.url?scp=84866530722&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84866530722&partnerID=8YFLogxK

U2 - 10.1073/pnas.1204166109

DO - 10.1073/pnas.1204166109

M3 - Article

C2 - 22949634

AN - SCOPUS:84866530722

VL - 109

SP - 15324

EP - 15329

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 38

ER -