Tgif1 Counterbalances the Activity of Core Pluripotency Factors in Mouse Embryonic Stem Cells

Bum-Kyu Lee; Wenwen Shen; Jiwoon Lee; Catherine Rhee; Haewon Chung; Kun-Yong Kim; In-Hyun Park; Jonghwan Kim

doi:10.1016/j.celrep.2015.08.067

Tgif1 Counterbalances the Activity of Core Pluripotency Factors in Mouse Embryonic Stem Cells

Cell Rep. 2015 Oct 6;13(1):52-60. doi: 10.1016/j.celrep.2015.08.067. Epub 2015 Sep 24.

Authors

Bum-Kyu Lee¹, Wenwen Shen², Jiwoon Lee¹, Catherine Rhee¹, Haewon Chung¹, Kun-Yong Kim³, In-Hyun Park³, Jonghwan Kim⁴

Affiliations

¹ Department of Molecular Biosciences, the University of Texas at Austin, Austin, TX 78712, USA; Institute for Cellular and Molecular Biology, Center for Systems and Synthetic Biology, the University of Texas at Austin, Austin, TX 78712, USA.
² Department of Molecular Biosciences, the University of Texas at Austin, Austin, TX 78712, USA.
³ Department of Genetics, Yale Stem Cell Center, Yale School of Medicine, 10 Amistad, 201B, New Haven, CT 06520, USA.
⁴ Department of Molecular Biosciences, the University of Texas at Austin, Austin, TX 78712, USA; Institute for Cellular and Molecular Biology, Center for Systems and Synthetic Biology, the University of Texas at Austin, Austin, TX 78712, USA. Electronic address: jonghwankim@mail.utexas.edu.

PMID: 26411691
DOI: 10.1016/j.celrep.2015.08.067

Abstract

Core pluripotency factors, such as Oct4, Sox2, and Nanog, play important roles in maintaining embryonic stem cell (ESC) identity by autoregulatory feedforward loops. Nevertheless, the mechanism that provides precise control of the levels of the ESC core factors without indefinite amplification has remained elusive. Here, we report the direct repression of core pluripotency factors by Tgif1, a previously known terminal repressor of TGFβ/activin/nodal signaling. Overexpression of Tgif1 reduces the levels of ESC core factors, whereas its depletion leads to the induction of the pluripotency factors. We confirm the existence of physical associations between Tgif1 and Oct4, Nanog, and HDAC1/2 and further show the level of Tgif1 is not significantly altered by treatment with an activator/inhibitor of the TGFβ/activin/nodal signaling. Collectively, our findings establish Tgif1 as an integral member of the core regulatory circuitry of mouse ESCs that counterbalances the levels of the core pluripotency factors in a TGFβ/activin/nodal-independent manner.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Activins / genetics
Activins / metabolism
Animals
Cell Differentiation
Ectoderm / cytology
Ectoderm / metabolism
Embryo, Mammalian
Endoderm / cytology
Endoderm / metabolism
Feedback, Physiological
Gene Expression Regulation, Developmental
Histone Deacetylase 1 / genetics
Histone Deacetylase 1 / metabolism
Histone Deacetylase 2 / genetics
Histone Deacetylase 2 / metabolism
Homeodomain Proteins / genetics*
Homeodomain Proteins / metabolism
Mesoderm / cytology
Mesoderm / metabolism
Mice
Mouse Embryonic Stem Cells / cytology
Mouse Embryonic Stem Cells / metabolism*
Nanog Homeobox Protein
Octamer Transcription Factor-3 / genetics*
Octamer Transcription Factor-3 / metabolism
Pluripotent Stem Cells / cytology
Pluripotent Stem Cells / metabolism
Repressor Proteins / genetics*
Repressor Proteins / metabolism
SOXB1 Transcription Factors / genetics*
SOXB1 Transcription Factors / metabolism
Signal Transduction
Transforming Growth Factor beta / genetics
Transforming Growth Factor beta / metabolism

Substances

Homeodomain Proteins
Nanog Homeobox Protein
Nanog protein, mouse
Octamer Transcription Factor-3
Pou5f1 protein, mouse
Repressor Proteins
SOXB1 Transcription Factors
Sox2 protein, mouse
Tgif1 protein, mouse
Transforming Growth Factor beta
Activins
Hdac1 protein, mouse
Hdac2 protein, mouse
Histone Deacetylase 1
Histone Deacetylase 2

Associated data

GEO/GSE55401
GEO/GSE55404