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

• Published in: Nature (London) Vol. 516; no. 7531; pp. 405 - 409
• Main Authors: Wang, Jichang, Xie, Gangcai, Singh, Manvendra, Ghanbarian, Avazeh T., Raskó, Tamás, Szvetnik, Attila, Cai, Huiqiang, Besser, Daniel, Prigione, Alessandro, Fuchs, Nina V., Schumann, Gerald G., Chen, Wei, Lorincz, Matthew C., Ivics, Zoltán, Hurst, Laurence D., Izsvák, Zsuzsanna
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18.12.2014; Nature Publishing Group
• Subjects: 13; 13/100; 13/44; 13/89; 45; 45/61; 45/91; 631/532; Cells, Cultured; DNA methylation; DNA Transposable Elements; Embryonic Stem Cells - cytology; Embryonic Stem Cells - metabolism; Endogenous Retroviruses - genetics; Endogenous Retroviruses - metabolism; Gene expression; Gene Expression Profiling; Genetic Markers; Humanities and Social Sciences; Humans; Induced Pluripotent Stem Cells - cytology; Induced Pluripotent Stem Cells - physiology; Induced Pluripotent Stem Cells - virology; letter; Monkeys & apes; multidisciplinary; RNA, Long Noncoding - metabolism; Science; Stem cells; Transcription factors; Transcription Factors - metabolism
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature13804

An extensive analysis of HERVH (a primate-specific endogenous retrovirus) expression in human pluripotent stem cells is presented, identifying a sub-population of cells within cultured human embryonic stem cells and induced pluripotent stem cells that has characteristics of naive-state cells — the study provides evidence for a new primate-specific transcriptional circuitry regulating pluripotency. Retroviral involvement in stem cell pluripotency This extensive analysis of human induced pluripotent stem (iPS) and embryonic stem (ES) cells identifies a subpopulation of cells that show elevated transcription of primate-specific endogenous retrovirus HERVH and display characteristics of naive-state cells. HERVH and the transcription factor LBP9 are shown to drive expression of transcripts specific to pluripotent cells, including regulatory long non-coding RNAs. The authors suggest that these findings point to the existence of a previously unrecognized primate-specific transcriptional circuitry regulating pluripotency. 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 easily 1 , 2 , although human naive-like cells have been artificially generated (rather than extracted) by coercion of human primed embryonic stem cells by modifying culture conditions 2 , 3 , 4 or through transgenic modification 5 . 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 mice 6 . 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.