{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T20:23:31Z","timestamp":1790195011771,"version":"4.1.0"},"reference-count":70,"publisher":"Springer Science and Business Media LLC","license":[{"start":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T00:00:00Z","timestamp":1782345600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T00:00:00Z","timestamp":1784678400000},"content-version":"vor","delay-in-days":27,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nature"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Understanding how the first cell lineages in human development are specified and maintained has fundamental importance and clinical implications for regenerative medicine, infertility and pregnancy loss. Although mouse models have provided valuable insights into transcription factors regulating early development, translating these findings to human embryos has been limited by ethical, technical and biological constraints. Functional studies of transcription factors in human embryos have been hindered by nuclease-based genome editing approaches that induce genotoxicity\n                    <jats:sup>1\u20133<\/jats:sup>\n                    . Here, to overcome this, we applied ABE8e adenine base editing\n                    <jats:sup>4,5<\/jats:sup>\n                    to precisely target an exon splice donor site, resulting in a splicing defect and functional knockout of the developmental regulator\n                    <jats:italic>NANOG<\/jats:italic>\n                    in human embryos. This approach did not trigger genotoxicity and showed limited off-target editing. Loss of\n                    <jats:italic>NANOG<\/jats:italic>\n                    disrupts pluripotent epiblast specification and instead cells differentiate towards a primitive endoderm (yolk sac) or trophectoderm (placental) transcriptional programme. Retention of primitive endoderm differentiation in\n                    <jats:italic>NANOG<\/jats:italic>\n                    -edited human embryos reveals a functional compensation that is distinct from mouse, underscoring the importance of directly investigating human development. Our findings demonstrate an essential role for NANOG in human pluripotency and epiblast specification and highlight the utility of base editing for functional interrogation of human development.\n                  <\/jats:p>","DOI":"10.1038\/s41586-026-10792-1","type":"journal-article","created":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T15:02:10Z","timestamp":1782399730000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Base editing reveals an essential role for NANOG in human embryogenesis"],"prefix":"10.1038","author":[{"given":"Oliver J.","family":"Bower","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4939-1423","authenticated-orcid":false,"given":"Ana E.","family":"R. Orsi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riley","family":"McMahon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1330-2158","authenticated-orcid":false,"given":"Desislava","family":"Staneva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2765-3514","authenticated-orcid":false,"given":"Josephine R.","family":"Blagrove","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9891-8148","authenticated-orcid":false,"given":"Kashish","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9614-1403","authenticated-orcid":false,"given":"Claire S.","family":"Simon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Afshan","family":"McCarthy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-9499-9401","authenticated-orcid":false,"given":"Patricia","family":"Garcia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie","family":"Shaikly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed","family":"Taranissi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1829-6850","authenticated-orcid":false,"given":"Martin","family":"Wilding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Serhal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rabi A.","family":"Odia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mina","family":"Vasilic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meenakshi","family":"Choudhary","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Athanasios","family":"Papathanasiou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3510-8268","authenticated-orcid":false,"given":"Kay","family":"Elder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phil","family":"Snell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leila","family":"Christie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mandana","family":"Arbab","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David R.","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary","family":"Herbert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2703-4342","authenticated-orcid":false,"given":"Katarina","family":"Harasimov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1646-4734","authenticated-orcid":false,"given":"Kathy K.","family":"Niakan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,25]]},"reference":[{"key":"10792_CR1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2004832117","volume":"118","author":"G Alanis-Lobato","year":"2021","unstructured":"Alanis-Lobato, G. et al. Frequent loss of heterozygosity in CRISPR-Cas9\u2013edited early human embryos. Proc. Natl Acad. Sci. USA 118, e2004832117 (2021).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"10792_CR2","doi-asserted-by":"publisher","first-page":"765","DOI":"10.1038\/nbt.4192","volume":"36","author":"M Kosicki","year":"2018","unstructured":"Kosicki, M., Tomberg, K. & Bradley, A. Repair of double-strand breaks induced by CRISPR\u2013Cas9 leads to large deletions and complex rearrangements. Nat. Biotechnol. 36, 765\u2013771 (2018).","journal-title":"Nat. Biotechnol."},{"key":"10792_CR3","doi-asserted-by":"publisher","first-page":"1650","DOI":"10.1016\/j.cell.2020.10.025","volume":"183","author":"MV Zuccaro","year":"2020","unstructured":"Zuccaro, M. V. et al. Allele-specific chromosome removal after Cas9 cleavage in human embryos. Cell 183, 1650\u20131664.e15 (2020).","journal-title":"Cell"},{"key":"10792_CR4","doi-asserted-by":"publisher","first-page":"464","DOI":"10.1038\/nature24644","volume":"551","author":"NM Gaudelli","year":"2017","unstructured":"Gaudelli, N. M. et al. Programmable base editing of A*T to G*C in genomic DNA without DNA cleavage. Nature 551, 464\u2013471 (2017).","journal-title":"Nature"},{"key":"10792_CR5","doi-asserted-by":"publisher","first-page":"883","DOI":"10.1038\/s41587-020-0453-z","volume":"38","author":"MF Richter","year":"2020","unstructured":"Richter, M. F. et al. Phage-assisted evolution of an adenine base editor with improved Cas domain compatibility and activity. Nat. Biotechnol. 38, 883\u2013891 (2020).","journal-title":"Nat. Biotechnol."},{"key":"10792_CR6","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1016\/S0092-8674(03)00392-1","volume":"113","author":"I Chambers","year":"2003","unstructured":"Chambers, I. et al. Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell 113, 643\u2013655 (2003).","journal-title":"Cell"},{"key":"10792_CR7","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1016\/S0092-8674(03)00393-3","volume":"113","author":"K Mitsui","year":"2003","unstructured":"Mitsui, K. et al. The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell 113, 631\u2013642 (2003).","journal-title":"Cell"},{"key":"10792_CR8","doi-asserted-by":"publisher","first-page":"947","DOI":"10.1016\/j.cell.2005.08.020","volume":"122","author":"LA Boyer","year":"2005","unstructured":"Boyer, L. A. et al. Core transcriptional regulatory circuitry in human embryonic stem cells. Cell 122, 947\u2013956 (2005).","journal-title":"Cell"},{"key":"10792_CR9","doi-asserted-by":"publisher","first-page":"722","DOI":"10.1016\/j.cell.2009.07.039","volume":"138","author":"J Silva","year":"2009","unstructured":"Silva, J. et al. Nanog Is the gateway to the pluripotent ground state. Cell 138, 722\u2013737 (2009).","journal-title":"Cell"},{"key":"10792_CR10","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1016\/j.devcel.2024.10.020","volume":"60","author":"AS Brumm","year":"2025","unstructured":"Brumm, A. S. et al. Initiation and maintenance of the pluripotent epiblast in pre-implantation human development is independent of NODAL signaling. Dev. Cell 60, 174\u2013185.e5 (2025).","journal-title":"Dev. Cell"},{"key":"10792_CR11","doi-asserted-by":"publisher","first-page":"1035","DOI":"10.1634\/stemcells.2005-0080","volume":"23","author":"L Hyslop","year":"2005","unstructured":"Hyslop, L. et al. Downregulation of NANOG induces differentiation of human embryonic stem cells to extraembryonic lineages. Stem Cells 23, 1035\u20131043 (2005).","journal-title":"Stem Cells"},{"key":"10792_CR12","doi-asserted-by":"publisher","first-page":"829","DOI":"10.1242\/dev.060426","volume":"139","author":"KK Niakan","year":"2012","unstructured":"Niakan, K. K., Han, J., Pedersen, R. A., Simon, C. & Pera, R. A. R. Human pre-implantation embryo development. Development 139, 829\u2013841 (2012).","journal-title":"Development"},{"key":"10792_CR13","doi-asserted-by":"publisher","first-page":"2988","DOI":"10.1016\/j.cell.2022.06.028","volume":"185","author":"KL Palmerola","year":"2022","unstructured":"Palmerola, K. L. et al. Replication stress impairs chromosome segregation and preimplantation development in human embryos. Cell 185, 2988\u20133007.e2920 (2022).","journal-title":"Cell"},{"key":"10792_CR14","doi-asserted-by":"publisher","first-page":"420","DOI":"10.1038\/nature17946","volume":"533","author":"AC Komor","year":"2016","unstructured":"Komor, A. C., Kim, Y. B., Packer, M. S., Zuris, J. A. & Liu, D. R. Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature 533, 420\u2013424 (2016).","journal-title":"Nature"},{"key":"10792_CR15","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-22009-2","volume":"12","author":"MG Kluesner","year":"2021","unstructured":"Kluesner, M. G. et al. CRISPR\u2013Cas9 cytidine and adenosine base editing of splice-sites mediates highly-efficient disruption of proteins in primary and immortalized cells. Nat. Commun. 12, 2437 (2021).","journal-title":"Nat. Commun."},{"key":"10792_CR16","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1038\/nature24033","volume":"550","author":"NME Fogarty","year":"2017","unstructured":"Fogarty, N. M. E. et al. Genome editing reveals a role for OCT4 in human embryogenesis. Nature 550, 67\u201373 (2017).","journal-title":"Nature"},{"key":"10792_CR17","doi-asserted-by":"publisher","first-page":"1931","DOI":"10.1634\/stemcells.2007-1002","volume":"26","author":"H Fong","year":"2008","unstructured":"Fong, H., Hohenstein, K. A. & Donovan, P. J. Regulation of self-renewal and pluripotency by Sox2 in human embryonic stem cells. Stem Cells 26, 1931\u20131938 (2008).","journal-title":"Stem Cells"},{"key":"10792_CR18","doi-asserted-by":"publisher","first-page":"1339","DOI":"10.1242\/dev.033951","volume":"136","author":"L Vallier","year":"2009","unstructured":"Vallier, L. et al. Activin\/Nodal signalling maintains pluripotency by controlling Nanog expression. Development 136, 1339\u20131349 (2009).","journal-title":"Development"},{"key":"10792_CR19","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1634\/stemcells.2004-0252","volume":"23","author":"H Zaehres","year":"2005","unstructured":"Zaehres, H. et al. High-efficiency RNA interference in human embryonic stem cells. Stem Cells 23, 299\u2013305 (2005).","journal-title":"Stem Cells"},{"key":"10792_CR20","doi-asserted-by":"publisher","first-page":"1040","DOI":"10.1016\/j.stem.2021.02.025","volume":"28","author":"G Guo","year":"2021","unstructured":"Guo, G. et al. Human naive epiblast cells possess unrestricted lineage potential. Cell Stem Cell 28, 1040\u20131056.e6 (2021).","journal-title":"Cell Stem Cell"},{"key":"10792_CR21","doi-asserted-by":"publisher","DOI":"10.1242\/dev.201155","volume":"150","author":"K Maskalenka","year":"2023","unstructured":"Maskalenka, K. et al. NANOGP1, a tandem duplicate of NANOG, exhibits partial functional conservation in human na\u00efve pluripotent stem cells. Development 150, dev201155 (2023).","journal-title":"Development"},{"key":"10792_CR22","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1016\/j.stem.2009.05.015","volume":"4","author":"J Nichols","year":"2009","unstructured":"Nichols, J. & Smith, A. Naive and primed pluripotent states. Cell Stem Cell 4, 487\u2013492 (2009).","journal-title":"Cell Stem Cell"},{"key":"10792_CR23","doi-asserted-by":"publisher","DOI":"10.1002\/cpz1.232","volume":"1","author":"OJ Bower","year":"2021","unstructured":"Bower, O. J. et al. Generating CRISPR\u2013Cas9-mediated null mutations and screening targeting efficiency in human pluripotent stem cells. Curr. Protoc. 1, e232 (2021).","journal-title":"Curr. Protoc."},{"key":"10792_CR24","doi-asserted-by":"publisher","first-page":"1230","DOI":"10.1038\/nature06403","volume":"450","author":"I Chambers","year":"2007","unstructured":"Chambers, I. et al. Nanog safeguards pluripotency and mediates germline development. Nature 450, 1230\u20131234 (2007).","journal-title":"Nature"},{"key":"10792_CR25","doi-asserted-by":"publisher","first-page":"332","DOI":"10.1016\/j.celrep.2017.12.060","volume":"22","author":"M Zhang","year":"2018","unstructured":"Zhang, M. et al. Esrrb complementation rescues development of Nanog-null germ cells. Cell Rep. 22, 332\u2013339 (2018).","journal-title":"Cell Rep."},{"key":"10792_CR26","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1016\/j.ydbio.2014.06.002","volume":"392","author":"LT Sun","year":"2014","unstructured":"Sun, L. T. et al. Nanog co-regulated by Nodal\/Smad2 and Oct4 is required for pluripotency in developing mouse epiblast. Dev. Biol. 392, 182\u2013192 (2014).","journal-title":"Dev. Biol."},{"key":"10792_CR27","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-24184-8","volume":"12","author":"A Sheriff","year":"2022","unstructured":"Sheriff, A. et al. ABE8e adenine base editor precisely and efficiently corrects a recurrent COL7A1 nonsense mutation. Sci. Rep. 12, 19643 (2022).","journal-title":"Sci. Rep."},{"key":"10792_CR28","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1038\/nature23305","volume":"548","author":"H Ma","year":"2017","unstructured":"Ma, H. et al. Correction of a pathogenic gene mutation in human embryos. Nature 548, 413\u2013419 (2017).","journal-title":"Nature"},{"key":"10792_CR29","doi-asserted-by":"publisher","first-page":"1022","DOI":"10.1016\/S0015-0282(98)00342-2","volume":"70","author":"GM Jones","year":"1998","unstructured":"Jones, G. M., Trounson, A. O., Lolatgis, N. & Wood, C. Factors affecting the success of human blastocyst development and pregnancy following in vitro fertilization and embryo transfer. Fertil. Steril. 70, 1022\u20131029 (1998).","journal-title":"Fertil. Steril."},{"key":"10792_CR30","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-023-01231-1","volume":"15","author":"RC McCoy","year":"2023","unstructured":"McCoy, R. C. et al. Meiotic and mitotic aneuploidies drive arrest of in vitro fertilized human preimplantation embryos. Genome Med. 15, 77 (2023).","journal-title":"Genome Med."},{"key":"10792_CR31","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1038\/s41586-019-1161-z","volume":"569","author":"J Gr\u00fcnewald","year":"2019","unstructured":"Gr\u00fcnewald, J. et al. Transcriptome-wide off-target RNA editing induced by CRISPR-guided DNA base editors. Nature 569, 433\u2013437 (2019).","journal-title":"Nature"},{"key":"10792_CR32","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aax5717","volume":"5","author":"HA Rees","year":"2019","unstructured":"Rees, H. A., Wilson, C., Doman, J. L. & Liu, D. R. Analysis and minimization of cellular RNA editing by DNA adenine base editors. Sci. Adv. 5, eaax5717 (2019).","journal-title":"Sci. Adv."},{"key":"10792_CR33","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1038\/s41586-019-1314-0","volume":"571","author":"C Zhou","year":"2019","unstructured":"Zhou, C. et al. Off-target RNA mutation induced by DNA base editing and its elimination by mutagenesis. Nature 571, 275\u2013278 (2019).","journal-title":"Nature"},{"key":"10792_CR34","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-024-03434-0","volume":"25","author":"L Wu","year":"2024","unstructured":"Wu, L. et al. Adenine base editors induce off-target structure variations in mouse embryos and primary human T cells. Genome Biol. 25, 291 (2024).","journal-title":"Genome Biol."},{"key":"10792_CR35","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-30858-8","volume":"13","author":"N Allegre","year":"2022","unstructured":"Allegre, N. et al. NANOG initiates epiblast fate through the coordination of pluripotency genes expression. Nat. Commun. 13, 3550 (2022).","journal-title":"Nat. Commun."},{"key":"10792_CR36","doi-asserted-by":"publisher","first-page":"1005","DOI":"10.1016\/j.devcel.2011.10.019","volume":"21","author":"S Frankenberg","year":"2011","unstructured":"Frankenberg, S. et al. Primitive endoderm differentiates via a three-step mechanism involving Nanog and RTK signaling. Dev. Cell 21, 1005\u20131013 (2011).","journal-title":"Dev. Cell"},{"key":"10792_CR37","doi-asserted-by":"publisher","first-page":"3151","DOI":"10.1242\/dev.131235","volume":"142","author":"P Blakeley","year":"2015","unstructured":"Blakeley, P. et al. Defining the three cell lineages of the human blastocyst by single-cell RNA-seq. Development 142, 3151\u20133165 (2015).","journal-title":"Development"},{"key":"10792_CR38","doi-asserted-by":"publisher","first-page":"1625","DOI":"10.1016\/j.stem.2021.04.027","volume":"28","author":"D Meistermann","year":"2021","unstructured":"Meistermann, D. et al. Integrated pseudotime analysis of human pre-implantation embryo single-cell transcriptomes reveals the dynamics of lineage specification. Cell Stem Cell 28, 1625\u20131640.e6 (2021).","journal-title":"Cell Stem Cell"},{"key":"10792_CR39","doi-asserted-by":"publisher","first-page":"1012","DOI":"10.1016\/j.cell.2016.03.023","volume":"165","author":"S Petropoulos","year":"2016","unstructured":"Petropoulos, S. et al. Single-cell RNA-seq reveals lineage and X chromosome dynamics in human preimplantation embryos. Cell 165, 1012\u20131026 (2016).","journal-title":"Cell"},{"key":"10792_CR40","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1038\/s41586-019-1127-1","volume":"569","author":"S Nowotschin","year":"2019","unstructured":"Nowotschin, S. et al. The emergent landscape of the mouse gut endoderm at single-cell resolution. Nature 569, 361\u2013367 (2019).","journal-title":"Nature"},{"key":"10792_CR41","doi-asserted-by":"publisher","first-page":"615","DOI":"10.1016\/j.devcel.2006.02.020","volume":"10","author":"C Chazaud","year":"2006","unstructured":"Chazaud, C., Yamanaka, Y., Pawson, T. & Rossant, J. Early lineage segregation between epiblast and primitive endoderm in mouse blastocysts through the Grb2\u2013MAPK pathway. Dev. Cell 10, 615\u2013624 (2006).","journal-title":"Dev. Cell"},{"key":"10792_CR42","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1016\/j.devcel.2017.05.003","volume":"41","author":"M Kang","year":"2017","unstructured":"Kang, M., Garg, V. & Hadjantonakis, A.-K. Lineage establishment and progression within the inner cell mass of the mouse blastocyst requires FGFR1 and FGFR2. Dev. Cell 41, 496\u2013510.e5 (2017).","journal-title":"Dev. Cell"},{"key":"10792_CR43","doi-asserted-by":"publisher","first-page":"1058","DOI":"10.1016\/j.stem.2024.05.003","volume":"31","author":"A Dattani","year":"2024","unstructured":"Dattani, A. et al. Naive pluripotent stem cell-based models capture FGF-dependent human hypoblast lineage specification. Cell Stem Cell 31, 1058\u20131071.e5 (2024).","journal-title":"Cell Stem Cell"},{"key":"10792_CR44","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-61830-x","volume":"16","author":"CS Simon","year":"2025","unstructured":"Simon, C. S. et al. Suppression of ERK signalling promotes pluripotent epiblast in the human blastocyst. Nat. Commun. 16, 6922 (2025).","journal-title":"Nat. Commun."},{"key":"10792_CR45","doi-asserted-by":"publisher","first-page":"6566","DOI":"10.1016\/j.cell.2024.08.048","volume":"187","author":"DP Iyer","year":"2024","unstructured":"Iyer, D. P. et al. mTOR activity paces human blastocyst stage developmental progression. Cell 187, 6566\u20136583.e22 (2024).","journal-title":"Cell"},{"key":"10792_CR46","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-14629-x","volume":"11","author":"SE Wamaitha","year":"2020","unstructured":"Wamaitha, S. E. et al. IGF1-mediated human embryonic stem cell self-renewal recapitulates the embryonic niche. Nat. Commun. 11, 764 (2020).","journal-title":"Nat. Commun."},{"key":"10792_CR47","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-41331-5","volume":"14","author":"H Zeng","year":"2023","unstructured":"Zeng, H. et al. A split and inducible adenine base editor for precise in vivo base editing. Nat. Commun. 14, 5573 (2023).","journal-title":"Nat. Commun."},{"key":"10792_CR48","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1007\/s10529-021-03214-x","volume":"44","author":"XX Zhu","year":"2022","unstructured":"Zhu, X. X. et al. Adenine base-editing-mediated exon skipping induces gene knockout in cultured pig cells. Biotechnol. Lett. 44, 59\u201376 (2022).","journal-title":"Biotechnol. Lett."},{"key":"10792_CR49","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-45969-7","volume":"15","author":"E Zhang","year":"2024","unstructured":"Zhang, E., Neugebauer, M. E., Krasnow, N. A. & Liu, D. R. Phage-assisted evolution of highly active cytosine base editors with enhanced selectivity and minimal sequence context preference. Nat. Commun. 15, 1697 (2024).","journal-title":"Nat. Commun."},{"key":"10792_CR50","unstructured":"International Commission on the Clinical Use of Human Germline Genome Editing. Heritable Human Genome Editing Ch. 5 (National Academies Press, 2020)."},{"key":"10792_CR51","doi-asserted-by":"publisher","first-page":"1398","DOI":"10.1016\/j.stemcr.2021.05.012","volume":"16","author":"R Lovell-Badge","year":"2021","unstructured":"Lovell-Badge, R. et al. ISSCR Guidelines for Stem Cell Research and Clinical Translation: the 2021 update. Stem Cell Rep. 16, 1398\u20131408 (2021).","journal-title":"Stem Cell Rep."},{"key":"10792_CR52","unstructured":"Committee on Human Gene Editing: Scientific, Medical, and Ethical Considerations. Human Genome Editing: Science, Ethics, and Governance Ch. 8 (National Academies Press, 2017)."},{"key":"10792_CR53","doi-asserted-by":"publisher","first-page":"1089","DOI":"10.1038\/s41596-020-00450-9","volume":"16","author":"TP Huang","year":"2021","unstructured":"Huang, T. P., Newby, G. A. & Liu, D. R. Precision genome editing using cytosine and adenine base editors in mammalian cells. Nat. Protoc. 16, 1089\u20131128 (2021).","journal-title":"Nat. Protoc."},{"key":"10792_CR54","unstructured":"Nagy, A. Manipulating the Mouse Embryo: a Laboratory Manual 3rd edn (Cold Spring Harbor Laboratory Press, 2003)."},{"key":"10792_CR55","doi-asserted-by":"publisher","first-page":"W242","DOI":"10.1093\/nar\/gky354","volume":"46","author":"J-P Concordet","year":"2018","unstructured":"Concordet, J.-P. & Haeussler, M. CRISPOR: intuitive guide selection for CRISPR\/Cas9 genome editing experiments and screens. Nucleic Acids Res. 46, W242\u2013W245 (2018).","journal-title":"Nucleic Acids Res."},{"key":"10792_CR56","doi-asserted-by":"publisher","first-page":"819","DOI":"10.1126\/science.1231143","volume":"339","author":"L Cong","year":"2013","unstructured":"Cong, L. et al. Multiplex genome engineering using CRISPR\/Cas systems. Science 339, 819\u2013823 (2013).","journal-title":"Science"},{"key":"10792_CR57","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1093\/bioinformatics\/btp698","volume":"26","author":"H Li","year":"2010","unstructured":"Li, H. & Durbin, R. Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics 26, 589\u2013595 (2010).","journal-title":"Bioinformatics"},{"key":"10792_CR58","doi-asserted-by":"publisher","first-page":"2078","DOI":"10.1093\/bioinformatics\/btp352","volume":"25","author":"H Li","year":"2009","unstructured":"Li, H. et al. The Sequence Alignment\/Map format and SAMtools. Bioinformatics 25, 2078\u20132079 (2009).","journal-title":"Bioinformatics"},{"key":"10792_CR59","doi-asserted-by":"publisher","first-page":"701","DOI":"10.1038\/nbt.3628","volume":"34","author":"H Lindsay","year":"2016","unstructured":"Lindsay, H. et al. CrispRVariants charts the mutation spectrum of genome engineering experiments. Nat. Biotechnol. 34, 701\u2013702 (2016).","journal-title":"Nat. Biotechnol."},{"key":"10792_CR60","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1038\/s41587-019-0032-3","volume":"37","author":"K Clement","year":"2019","unstructured":"Clement, K. et al. CRISPResso2 provides accurate and rapid genome editing sequence analysis. Nat. Biotechnol. 37, 224\u2013226 (2019).","journal-title":"Nat. Biotechnol."},{"key":"10792_CR61","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","volume":"29","author":"A Dobin","year":"2013","unstructured":"Dobin, A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15\u201321 (2013).","journal-title":"Bioinformatics"},{"key":"10792_CR62","doi-asserted-by":"publisher","first-page":"907","DOI":"10.1038\/s41587-019-0201-4","volume":"37","author":"D Kim","year":"2019","unstructured":"Kim, D., Paggi, J. M., Park, C., Bennett, C. & Salzberg, S. L. Graph-based genome alignment and genotyping with HISAT2 and HISAT-genotype. Nat. Biotechnol. 37, 907\u2013915 (2019).","journal-title":"Nat. Biotechnol."},{"key":"10792_CR63","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1093\/bioinformatics\/btu638","volume":"31","author":"S Anders","year":"2015","unstructured":"Anders, S., Pyl, P. T. & Huber, W. HTSeq\u2013a Python framework to work with high-throughput sequencing data. Bioinformatics 31, 166\u2013169 (2015).","journal-title":"Bioinformatics"},{"key":"10792_CR64","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1038\/s41587-023-01767-y","volume":"42","author":"Y Hao","year":"2024","unstructured":"Hao, Y. et al. Dictionary learning for integrative, multimodal and scalable single-cell analysis. Nat. Biotechnol. 42, 293\u2013304 (2024).","journal-title":"Nat. Biotechnol."},{"key":"10792_CR65","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1186\/1471-2105-14-128","volume":"14","author":"EY Chen","year":"2013","unstructured":"Chen, E. Y. et al. Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinformatics 14, 128 (2013).","journal-title":"BMC Bioinformatics"},{"key":"10792_CR66","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8","volume":"15","author":"MI Love","year":"2014","unstructured":"Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).","journal-title":"Genome Biol."},{"key":"10792_CR67","doi-asserted-by":"publisher","DOI":"10.1186\/s12864-023-09523-x","volume":"24","author":"YH Jung","year":"2023","unstructured":"Jung, Y. H., Wang, H. V., Ali, S., Corces, V. G. & Kremsky, I. Characterization of a strain-specific CD-1 reference genome reveals potential inter- and intra-strain functional variability. BMC Genomics 24, 437 (2023).","journal-title":"BMC Genomics"},{"key":"10792_CR68","doi-asserted-by":"publisher","first-page":"D925","DOI":"10.1093\/nar\/gkae977","volume":"53","author":"L Phan","year":"2025","unstructured":"Phan, L. et al. The evolution of dbSNP: 25 years of impact in genomic research. Nucleic Acids Res. 53, D925\u2013D931 (2025).","journal-title":"Nucleic Acids Res."},{"key":"10792_CR69","doi-asserted-by":"publisher","unstructured":"Harasimov, K. & Niakan, K. Base editing reveals an essential role for NANOG in human embryogenesis. Figshare https:\/\/doi.org\/10.6084\/m9.figshare.32336139.v3 (2026).","DOI":"10.6084\/m9.figshare.32336139.v3"},{"key":"10792_CR70","doi-asserted-by":"publisher","first-page":"2281","DOI":"10.1038\/nprot.2013.143","volume":"8","author":"FA Ran","year":"2013","unstructured":"Ran, F. A. et al. Genome engineering using the CRISPR\u2013Cas9 system. Nat. Protoc. 8, 2281\u20132308 (2013).","journal-title":"Nat. Protoc."}],"container-title":["Nature"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41586-026-10792-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41586-026-10792-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41586-026-10792-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T15:10:12Z","timestamp":1788966612000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41586-026-10792-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,25]]},"references-count":70,"alternative-id":["10792"],"URL":"https:\/\/doi.org\/10.1038\/s41586-026-10792-1","relation":{},"ISSN":["0028-0836","1476-4687"],"issn-type":[{"value":"0028-0836","type":"print"},{"value":"1476-4687","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,25]]},"assertion":[{"value":"16 July 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 June 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 June 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"D.R.L. is a co-founder of Beam Therapeutics, Prime Medicine, Editas Medicine, Pairwise Plants and nChroma Bio, companies that use or deliver genome editing agents, and a co-inventor on gene editing patents including foundational base editing and prime editing patents. After completing his PhD and his role in the project, O.J.B. became an employee of Preventive PBC, a public benefit corporation investigating the safety of gene editing technologies. The other authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}]}}