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The Role of CDX2 as a Lineage Specific Transcriptional Repressor for Pluripotent Network During Trophectoderm and Inner Cell Mass Specification

35 Pages Posted: 5 Apr 2018 Sneak Peek Status: Review Complete

See all articles by Daosheng Huang

Daosheng Huang

Zhejiang University - Center of Stem Cell and Regenerative Medicine

Xiaoping Han

Zhejiang University - Center of Stem Cell and Regenerative Medicine

Ping Yuan

Sun Yat-Sen University (SYSU) - Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases

Amy Ralston

Michigan State University - Department of Biochemistry & Molecular Biology

Lingang Sun

Zhejiang University - Center of Stem Cell and Regenerative Medicine

Mikael Huss

Royal Institute of Technology (KTH) - Science for Life Laboratory

Tapan Mistri

University of Edinburgh - Centre for Regenerative Medicine (Institute for Stem Cell Research)

Luca Pinello

Dana-Farber/Harvard Cancer Center - Department of Biostatistics and Computational Biology

Huck Hui Ng

Agency for Science, Technology and Research (A*STAR) - Stem Cell and Regenerative Biology

Guocheng Yuan

Dana-Farber/Harvard Cancer Center - Department of Biostatistics and Computational Biology; Harvard University - T.H. Chan School of Public Health

Junfeng Ji

Zhejiang University - Center of Stem Cell and Regenerative Medicine

Janet Rossant

University of Toronto - Developmental & Stem Cell Biology Program

Paul Robson

The Jackson Laboratory - Jackson Laboratory for Genomic Medicine

Guoji Guo

Zhejiang University - Center of Stem Cell and Regenerative Medicine

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Abstract

The first cellular differentiation event in mouse development leads to the formation of the blastocyst consisting of the inner cell mass (ICM) and an outer functional epithelium called trophectoderm (TE). The lineage specific transcription factor CDX2 is required for proper TE specification, where it promotes expression of TE genes, and represses expression of Pou5f1 (OCT4) by inhibiting OCT4 from promoting its own expression. However its downstream network in the developing early embryo is not fully characterized. Here, we performed high ‐ throughput single embryo qPCR analysis in Cdx2 null embryos to identify components of the CDX2 ‐ regulated network in vivo. To identify genes likely to be regulated by CDX2 directly, we performed CDX2 ChIP ‐ Seq on trophoblast stem (TS) cells, derived from the TE. In addition, we examined the dynamics of gene expression changes using an inducible CDX2 embryonic stem (ES) cell system, so that we could predict which CDX2 ‐ bound genes are activated or repressed by CDX2 binding. By integrating these data with observations of chromatin modifications, we were able to identify novel regulatory elements that are likely to repress gene expression in a lineage ‐ specific manner. Interestingly, we found CDX2 binding sites within regulatory elements of key pluripotent genes such as Pou5f1 and Nanog, pointing to the existence of a novel mechanism by which CDX2 maintains repression of OCT4 in trophoblast. Our study proposes a general mechanism in regulating lineage segregation during mammalian development.

Keywords: Lineage Segregation, Trophectoderm, Inner Cell Mass, CDX2, Transcription Repression, Cell Fate Decision

Suggested Citation

Huang, Daosheng and Han, Xiaoping and Yuan, Ping and Ralston, Amy and Sun, Lingang and Huss, Mikael and Mistri, Tapan and Pinello, Luca and Ng, Huck Hui and Yuan, Guocheng and Ji, Junfeng and Rossant, Janet and Robson, Paul and Guo, Guoji, The Role of CDX2 as a Lineage Specific Transcriptional Repressor for Pluripotent Network During Trophectoderm and Inner Cell Mass Specification (2018). Available at SSRN: https://ssrn.com/abstract=3155567 or http://dx.doi.org/10.2139/ssrn.3155567
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Daosheng Huang

Zhejiang University - Center of Stem Cell and Regenerative Medicine

866 Yuhangtang Road
Hangzhou, 310058
China

Xiaoping Han

Zhejiang University - Center of Stem Cell and Regenerative Medicine

866 Yuhangtang Road
Hangzhou, 310058
China

Ping Yuan

Sun Yat-Sen University (SYSU) - Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases

26 Yuancun Erheng Rd
Guangzhou, 510655
China

Amy Ralston

Michigan State University - Department of Biochemistry & Molecular Biology

603 Wilson Rd
East Lansing, MI 48823
United States

Lingang Sun

Zhejiang University - Center of Stem Cell and Regenerative Medicine

866 Yuhangtang Road
Hangzhou, 310058
China

Mikael Huss

Royal Institute of Technology (KTH) - Science for Life Laboratory

Stockholm, SE-100 44
Sweden

Tapan Mistri

University of Edinburgh - Centre for Regenerative Medicine (Institute for Stem Cell Research)

5 Little France Drive
Edinburgh, Scotland
United Kingdom

Luca Pinello

Dana-Farber/Harvard Cancer Center - Department of Biostatistics and Computational Biology

450 Brookline Avenue
Boston, MA 02215
United States

Huck Hui Ng

Agency for Science, Technology and Research (A*STAR) - Stem Cell and Regenerative Biology

60 Biopolis Street
138672
Singapore

Guocheng Yuan

Dana-Farber/Harvard Cancer Center - Department of Biostatistics and Computational Biology

450 Brookline Avenue
Boston, MA 02215
United States

Harvard University - T.H. Chan School of Public Health

677 Huntington Avenue
Boston, MA MA 02115
United States

Junfeng Ji

Zhejiang University - Center of Stem Cell and Regenerative Medicine

866 Yuhangtang Road
Hangzhou, 310058
China

Janet Rossant

University of Toronto - Developmental & Stem Cell Biology Program

Toronto, Ontario
Canada

Paul Robson

The Jackson Laboratory - Jackson Laboratory for Genomic Medicine

10 Discovery Dr
Farmington, CT 06032
United States

Guoji Guo (Contact Author)

Zhejiang University - Center of Stem Cell and Regenerative Medicine ( email )

866 Yuhangtang Road
Hangzhou, 310058
China

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