Klf5 establishes bi-potential cell fate by dual regulation of ICM and TE specification genes

Martin Kinisu; Yong Jin Choi; Claudia Cattoglio; Ke Liu; Hector Roux de Bezieux; Raeline Valbuena; Nicole Pum; Sandrine Dudoit; Haiyan Huang; Zhenyu Xuan; Sang Yong Kim; Lin He

doi:10.1016/j.celrep.2021.109982

Klf5 establishes bi-potential cell fate by dual regulation of ICM and TE specification genes

Cell Rep. 2021 Nov 9;37(6):109982. doi: 10.1016/j.celrep.2021.109982.

Authors

Affiliations

¹ Division of Cellular and Developmental Biology, MCB Department, University of California, Berkeley, Berkeley, CA 94705, USA.
² Division of Cellular and Developmental Biology, MCB Department, University of California, Berkeley, Berkeley, CA 94705, USA; Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA 94720, USA.
³ Department of Statistics, University of California, Berkeley, Berkeley, CA 94720, USA.
⁴ Division of Biostatistics, School of Public Health, University of California, Berkeley, Berkeley, CA 94720, USA.
⁵ Department of Molecular and Cell Biology, University of Texas at Dallas, 800 West Campbell Road, Richardson, TX 75080, USA.
⁶ Department of Pathology, NYU Grossman School of Medicine, 540 First Avenue, New York, NY 10016, USA.
⁷ Division of Cellular and Developmental Biology, MCB Department, University of California, Berkeley, Berkeley, CA 94705, USA. Electronic address: lhe@berkeley.edu.

Abstract

Early blastomeres of mouse preimplantation embryos exhibit bi-potential cell fate, capable of generating both embryonic and extra-embryonic lineages in blastocysts. Here we identify three major two-cell-stage (2C)-specific endogenous retroviruses (ERVs) as the molecular hallmark of this bi-potential plasticity. Using the long terminal repeats (LTRs) of all three 2C-specific ERVs, we identify Krüppel-like factor 5 (Klf5) as their major upstream regulator. Klf5 is essential for bi-potential cell fate; a single Klf5-overexpressing embryonic stem cell (ESC) generates terminally differentiated embryonic and extra-embryonic lineages in chimeric embryos, and Klf5 directly induces inner cell mass (ICM) and trophectoderm (TE) specification genes. Intriguingly, Klf5 and Klf4 act redundantly during ICM specification, whereas Klf5 deficiency alone impairs TE specification. Klf5 is regulated by multiple 2C-specific transcription factors, particularly Dux, and the Dux/Klf5 axis is evolutionarily conserved. The 2C-specific transcription program converges on Klf5 to establish bi-potential cell fate, enabling a cell state with dual activation of ICM and TE genes.

Keywords: ICM; Klf4; Klf5; MERVL; ORR1A0; ORR1A1; TE; preimplantation development.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Blastocyst Inner Cell Mass / cytology*
Blastocyst Inner Cell Mass / metabolism
Blastocyst*
Cell Differentiation
Cell Lineage*
Embryonic Stem Cells / cytology*
Embryonic Stem Cells / metabolism
Female
Gene Expression Regulation, Developmental*
Kruppel-Like Transcription Factors / genetics
Kruppel-Like Transcription Factors / metabolism*
Male
Mice
Mice, Inbred C3H
Mice, Inbred C57BL
RNA-Seq
Transcription Factors / genetics
Transcription Factors / metabolism
Trophoblasts / cytology*
Trophoblasts / metabolism

Substances

Klf5 protein, mouse
Kruppel-Like Transcription Factors
Transcription Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding