![]() At the peak of their expression, MERVL, ORR1A0, and ORR1A1 each account for 5.3%, 1.5%, and 1.1% of all mapped reads in 2C blastomeres, respectively ( Figure S1A). Although MERVL induction is a prominent molecular hallmark of 2C blastomeres, two additional ERVs, ORR1A0 and ORR1A1, also constitute the major retrotransposon families with a 2C-specific expression pattern ( Figures 1B and 1C Figure S1A). Using published single-cell RNA sequencing (RNA-seq) data on preimplantation embryos, we observed a dynamic and tightly regulated expression pattern of retrotransposons ( Figure 1B Figure S1A). We set out to comprehensively identify 2C-specific retrotransposon markers in search of a master transcriptional regulator of bi-potential cell fate ( Figure 1A). 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. Klf5 is regulated by multiple 2C-specific transcription factors, particularly Dux, and the Dux/Klf5 axis is evolutionarily conserved. Intriguingly, Klf5 and Klf4 act redundantly during ICM specification, whereas Klf5 deficiency alone impairs TE specification. 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. Using the long terminal repeats (LTRs) of all three 2C-specific ERVs, we identify Krüppel-like factor 5 (Klf5) as their major upstream regulator. Here we identify three major two-cell-stage (2C)-specific endogenous retroviruses (ERVs) as the molecular hallmark of this bi-potential plasticity. Early blastomeres of mouse preimplantation embryos exhibit bi-potential cell fate, capable of generating both embryonic and extra-embryonic lineages in blastocysts.
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