Primate-specific endogenous retrovirus-driven transcription defines naive-like stem cells

Jichang Wang, Gangcai Xie, Manvendra Singh, Avazeh Tashakkori Ghanbarian, Tamás Raskó, Attila Szvetnik, Huiqiang Cai, Daniel Besser, Alessandro Prigione, Nina V. Fuchs, Gerald G. Schumann, Wei Chen, Matthew C. Lorincz, Zoltán Ivics, Laurence D. Hurst, Zsuzsanna Izsvák

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Abstract

Naive embryonic stem cells hold great promise for research and therapeutics as they have broad and robust developmental potential. While such cells are readily derived from mouse blastocysts it has not been possible to isolate human equivalents easily1, 2, although human naive-like cells have been artificially generated (rather than extracted) by coercion of human primed embryonic stem cells by modifying culture conditions2, 3, 4 or through transgenic modification5. Here we show that a sub-population within cultures of human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) manifests key properties of naive state cells. These naive-like cells can be genetically tagged, and are associated with elevated transcription of HERVH, a primate-specific endogenous retrovirus. HERVH elements provide functional binding sites for a combination of naive pluripotency transcription factors, including LBP9, recently recognized as relevant to naivety in mice6. LBP9–HERVH drives hESC-specific alternative and chimaeric transcripts, including pluripotency-modulating long non-coding RNAs. Disruption of LBP9, HERVH and HERVH-derived transcripts compromises self-renewal. These observations define HERVH expression as a hallmark of naive-like hESCs, and establish novel primate-specific transcriptional circuitry regulating pluripotency.
Original languageEnglish
Pages (from-to)405-409
Number of pages5
JournalNature
Volume516
Issue number7531
Early online date15 Oct 2014
DOIs
Publication statusPublished - 18 Dec 2014

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    Wang, J., Xie, G., Singh, M., Tashakkori Ghanbarian, A., Raskó, T., Szvetnik, A., Cai, H., Besser, D., Prigione, A., Fuchs, N. V., Schumann, G. G., Chen, W., Lorincz, M. C., Ivics, Z., Hurst, L. D., & Izsvák, Z. (2014). Primate-specific endogenous retrovirus-driven transcription defines naive-like stem cells. Nature, 516(7531), 405-409. https://doi.org/10.1038/nature13804