1. Klf5 establishes bi-potential cell fate by dual regulation of ICM and TE specification genes
- Author
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Sang Yong Kim, Haiyan Huang, Raeline Valbuena, Lin He, Claudia Cattoglio, Nicole Pum, Yong Jin Choi, Martin Kinisu, Zhenyu Xuan, Sandrine Dudoit, Ke Liu, and Hector Roux de Bézieux
- Subjects
Male ,1.1 Normal biological development and functioning ,Medical Physiology ,Kruppel-Like Transcription Factors ,Endogenous retrovirus ,Cell fate determination ,Biology ,Inbred C57BL ,MERVL ,Article ,General Biochemistry, Genetics and Molecular Biology ,Mice ,ORR1A1 ,Underpinning research ,Transcription (biology) ,ORR1A0 ,Animals ,Inner cell mass ,Developmental ,Cell Lineage ,RNA-Seq ,Transcription factor ,Embryonic Stem Cells ,Mice, Inbred C3H ,Gene Expression Regulation, Developmental ,Cell Differentiation ,Klf5 ,Stem Cell Research ,Inbred C3H ,Klf4 ,Embryonic stem cell ,ICM ,Long terminal repeat ,Trophoblasts ,Cell biology ,Mice, Inbred C57BL ,Blastocyst ,Gene Expression Regulation ,KLF4 ,Blastocyst Inner Cell Mass ,embryonic structures ,preimplantation development ,Female ,Stem Cell Research - Nonembryonic - Non-Human ,Generic health relevance ,Biochemistry and Cell Biology ,Transcription Factors ,TE - Abstract
SUMMARY 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., Graphical abstract, In brief Using multiple 2C-specific ERV cell fate markers, Kinisu et al. identify Klf5 as a key transcription factor that confers a 2C-like developmental potential and activates ICM and TE specification genes. Klf5 and Klf4 act redundantly for ICM and TE specification in mouse preimplantation embryos.
- Published
- 2021