Elevated retrotransposon activity and genomic instability in primed pluripotent stem cells.

Naive and primed pluripotent stem cells (PSCs) represent two different pluripotent states. Primed PSCs following in vitro culture exhibit lower developmental potency as evidenced by failure in germline chimera assays, unlike mouse naive PSCs. However, the molecular mechanisms underlying the lower developmental competency of primed PSCs remain elusive. We examine the regulation of telomere maintenance, retrotransposon activity, and genomic stability of primed PSCs and compare them with naive PSCs. Surprisingly, primed PSCs only minimally maintain telomeres and show fragile telomeres, associated with declined DNA recombination and repair activity, in contrast to naive PSCs that robustly elongate telomeres. Also, we identify LINE1 family integrant L1Md_T as naive-specific retrotransposon and ERVK family integrant IAPEz to define primed PSCs, and their transcription is differentially regulated by heterochromatic histones and Dnmt3b. Notably, genomic instability of primed PSCs is increased, in association with aberrant retrotransposon activity. Our data suggest that fragile telomere, retrotransposon-associated genomic instability, and declined DNA recombination repair, together with reduced function of cell cycle and mitochondria, increased apoptosis, and differentiation properties may link to compromised developmental potency of primed PSCs, noticeably distinguishable from naive PSCs.