title: Primate-specific endogenous retrovirus-driven transcription defines naive-like stem cells.
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 easily, although human naive-like cells have been artificially generated (rather than extracted) by coercion of human primed embryonic stem cells by modifying culture conditions or through transgenic modification. 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. 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.
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Jichang
authors.initials: J
authors.lastname: Wang
authors.affiliation: 1] Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany [2] Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, 320 Yueyang Road, Shanghai 200031, China.
authors.forename: Gangcai
authors.initials: G
authors.lastname: Xie
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Manvendra
authors.initials: M
authors.lastname: Singh
authors.affiliation: University of Bath, Department of Biology and Biochemistry, Bath, Somerset BA2 7AY, UK.
authors.forename: Avazeh T
authors.initials: AT
authors.lastname: Ghanbarian
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Tamás
authors.initials: T
authors.lastname: Raskó
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Attila
authors.initials: A
authors.lastname: Szvetnik
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Huiqiang
authors.initials: H
authors.lastname: Cai
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Besser
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Prigione
authors.affiliation: 1] Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany [2] Paul-Ehrlich-Institute, Division of Medical Biotechnology, Paul-Ehrlich-Strasse 51-59, 63225 Langen, Germany.
authors.forename: Nina V
authors.initials: NV
authors.lastname: Fuchs
authors.affiliation: Paul-Ehrlich-Institute, Division of Medical Biotechnology, Paul-Ehrlich-Strasse 51-59, 63225 Langen, Germany.
authors.forename: Gerald G
authors.initials: GG
authors.lastname: Schumann
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Lorincz
authors.affiliation: Paul-Ehrlich-Institute, Division of Medical Biotechnology, Paul-Ehrlich-Strasse 51-59, 63225 Langen, Germany.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Ivics
authors.affiliation: University of Bath, Department of Biology and Biochemistry, Bath, Somerset BA2 7AY, UK.
authors.forename: Laurence D
authors.initials: LD
authors.lastname: Hurst
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Izsvák
mesh_terms: D002478:Cells, Cultured; D004251:DNA Transposable Elements; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D020077:Endogenous Retroviruses / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D005819:Genetic Markers; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000502:physiology* / Q000821:virology; D062085:RNA, Long Noncoding / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D004251:DNA Transposable Elements; D005819:Genetic Markers; D062085:RNA, Long Noncoding; D014157:Transcription Factors