{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T01:45:59Z","timestamp":1776217559201,"version":"3.50.1"},"reference-count":40,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2021,11,23]],"date-time":"2021-11-23T00:00:00Z","timestamp":1637625600000},"content-version":"vor","delay-in-days":1964,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100001691","name":"World-Leading Innovative Research and Development on Science and Technology (FIRST Program) of Japan Society for the Promotion of Science","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Core Center for iPS Cell Research and Projects for Technological Development"},{"DOI":"10.13039\/501100002241","name":"Research Center Network for Realization of Regenerative Medicine in Japan Science and Technology Agency","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002241","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001700","name":"Grants-in-Aid for Scientific Research of JSPS and the Ministry of Education, Culture, Sports, Science, and Technology","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Grants-in-Aid for Scientific Research for Young Scientists B"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,11,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Gene screenings have identified a number of reprogramming factors that induce pluripotency from somatic cells. However, the screening methods have mostly considered only factors that maintain pluripotency in embryonic stem cells, ignoring a potentially long list of other contributing factors involved. To expand the search, we developed a new screening method that examined 2,008 human genes in the generation of human induced pluripotent stem cells (iPSCs), including not only pluripotent genes but also differentiation-related genes that suppress pluripotency. We found the top 100 genes that increased reprogramming efficiency and discovered they contained many differentiation-related genes and homeobox genes. We selected two, HHEX and HLX, for further analysis. These genes enhanced the appearance of premature reprograming cells in the early phase of human iPSC induction, but had inhibitory effect on the late phase. In addition, when expressed in human iPSCs, HHEX and HLX interfered with the pluripotent state, indicating inverse effects on somatic reprograming and pluripotent maintenance. These results demonstrate that our screening is useful for identifying differentiation-related genes in somatic reprograming.<\/jats:p>","DOI":"10.1002\/stem.2436","type":"journal-article","created":{"date-parts":[[2016,6,22]],"date-time":"2016-06-22T21:23:03Z","timestamp":1466630583000},"page":"2661-2669","source":"Crossref","is-referenced-by-count":8,"title":["Screening of Human cDNA Library Reveals Two differentiation-Related Genes,\n                    <i>HHEX<\/i>\n                    and\n                    <i>HLX<\/i>\n                    , as Promoters of Early Phase Reprogramming toward Pluripotency"],"prefix":"10.1093","volume":"34","author":[{"given":"Tatsuya","family":"Yamakawa","sequence":"first","affiliation":[{"name":"Center for iPS Cell Research and Application, Kyoto University , Kyoto,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshiko","family":"Sato","sequence":"additional","affiliation":[{"name":"Center for iPS Cell Research and Application, Kyoto University , Kyoto,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasuko","family":"Matsumura","sequence":"additional","affiliation":[{"name":"Center for iPS Cell Research and Application, Kyoto University , Kyoto,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yukiko","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Center for iPS Cell Research and Application, Kyoto University , Kyoto,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshifumi","family":"Kawamura","sequence":"additional","affiliation":[{"name":"Japan Biological Informatics Consortium , Tokyo,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naoki","family":"Goshima","sequence":"additional","affiliation":[{"name":"Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology , Tokyo,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shinya","family":"Yamanaka","sequence":"additional","affiliation":[{"name":"Center for iPS Cell Research and Application, Kyoto University , Kyoto,","place":["Japan"]},{"name":"Gladstone Institute of Cardiovascular Disease , San Francisco, California,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keisuke","family":"Okita","sequence":"additional","affiliation":[{"name":"Center for iPS Cell Research and Application, Kyoto University , Kyoto,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2016,7,8]]},"reference":[{"key":"2026041420241937700_stem2436-bib-0001","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1016\/j.cell.2007.11.019","article-title":"Induction of pluripotent stem cells from adult human fibroblasts by defined Factors","volume":"131","author":"Takahashi","year":"2007","journal-title":"Cell"},{"key":"2026041420241937700_stem2436-bib-0002","doi-asserted-by":"crossref","first-page":"1917","DOI":"10.1126\/science.1151526","article-title":"Induced pluripotent stem cell lines derived from human somatic Cells","volume":"318","author":"Yu","year":"2007","journal-title":"Science"},{"key":"2026041420241937700_stem2436-bib-0003","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1038\/ncb1827","article-title":"Reprogramming of fibroblasts into induced pluripotent stem cells with orphan nuclear receptor Esrrb","volume":"11","author":"Feng","year":"2009","journal-title":"Nat Cell Biol"},{"key":"2026041420241937700_stem2436-bib-0004","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1111\/j.1365-2443.2009.01301.x","article-title":"Roles of Sall4 in the generation of pluripotent stem cells from blastocysts and fibroblasts","volume":"14","author":"Tsubooka","year":"2009","journal-title":"Genes Cells"},{"key":"2026041420241937700_stem2436-bib-0005","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.stem.2009.12.009","article-title":"The nuclear receptor Nr5a2 can replace Oct4 in the reprogramming of murine somatic cells to pluripotent Cells","volume":"6","author":"Heng","year":"2010","journal-title":"Cell Stem Cell"},{"key":"2026041420241937700_stem2436-bib-0006","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1038\/nature08235","article-title":"Suppression of induced pluripotent stem cell generation by the p53\u2013p21 pathway","volume":"460","author":"Hong","year":"2009","journal-title":"Nature"},{"key":"2026041420241937700_stem2436-bib-0007","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1038\/nature08592","article-title":"Direct cell reprogramming is a stochastic process amenable to acceleration","volume":"462","author":"Hanna","year":"2009","journal-title":"Nature"},{"key":"2026041420241937700_stem2436-bib-0008","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1016\/j.stemcr.2014.07.006","article-title":"Transient p53 suppression increases reprogramming of human fibroblasts without affecting apoptosis and DNA Damage","volume":"3","author":"Rasmussen","year":"2014","journal-title":"Stem Cell Reports"},{"key":"2026041420241937700_stem2436-bib-0009","doi-asserted-by":"crossref","first-page":"3678","DOI":"10.1038\/ncomms4678","article-title":"Induction of pluripotency in human somatic cells via a transient state resembling primitive streak-like mesendoderm","volume":"5","author":"Takahashi","year":"2014","journal-title":"Nat Commun"},{"key":"2026041420241937700_stem2436-bib-0010","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1038\/nature10106","article-title":"Direct reprogramming of somatic cells is promoted by maternal transcription factor Glis1","volume":"474","author":"Maekawa","year":"2011","journal-title":"Nature"},{"key":"2026041420241937700_stem2436-bib-0011","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1038\/nature12587","article-title":"Deterministic direct reprogramming of somatic cells to pluripotency","volume":"502","author":"Rais","year":"2013","journal-title":"Nature"},{"key":"2026041420241937700_stem2436-bib-0012","doi-asserted-by":"crossref","first-page":"e1003112","DOI":"10.1371\/journal.pgen.1003112","article-title":"A genome-wide RNAi screen reveals MAP kinase phosphatases as key ERK pathway regulators during embryonic stem cell differentiation","volume":"8","author":"Yang","year":"2012","journal-title":"PLoS Genet"},{"key":"2026041420241937700_stem2436-bib-0013","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1101\/gad.1769609","article-title":"A genome-wide RNAi screen identifies a new transcriptional module required for self-renewal","volume":"23","author":"Hu","year":"2009","journal-title":"Genes Dev"},{"key":"2026041420241937700_stem2436-bib-0014","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1038\/nature09531","article-title":"A genome-wide RNAi screen reveals determinants of human embryonic stem cell identity","volume":"468","author":"Chia","year":"2010","journal-title":"Nature"},{"key":"2026041420241937700_stem2436-bib-0015","doi-asserted-by":"crossref","first-page":"2675","DOI":"10.1084\/jem.20102037","article-title":"A genome-wide RNAi screen in mouse embryonic stem cells identifies Mp1 as a key mediator of differentiation","volume":"208","author":"Westerman","year":"2011","journal-title":"J Exp Med"},{"key":"2026041420241937700_stem2436-bib-0016","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/j.stem.2009.03.009","article-title":"A Genome-scale RNAi screen for Oct4 modulators defines a role of the Paf1 complex for embryonic stem cell Identity","volume":"4","author":"Ding","year":"2009","journal-title":"Cell Stem Cell"},{"key":"2026041420241937700_stem2436-bib-0017","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1038\/nature04915","article-title":"Dissecting self-renewal in stem cells with RNA interference","volume":"442","author":"Ivanova","year":"2006","journal-title":"Nature"},{"key":"2026041420241937700_stem2436-bib-0018","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.molcel.2014.08.014","article-title":"A Genome-wide RNAi screen identifies opposing functions of Snai1 and Snai2 on the nanog dependency in Reprogramming","volume":"56","author":"Gingold","year":"2014","journal-title":"Mol Cell"},{"key":"2026041420241937700_stem2436-bib-0019","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1101\/gad.1279405","article-title":"Heart induction by wnt antagonists depends on the homeodomain transcription factor Hex","volume":"19","author":"Foley","year":"2005","journal-title":"Genes Dev"},{"key":"2026041420241937700_stem2436-bib-0020","doi-asserted-by":"crossref","first-page":"2303","DOI":"10.1242\/dev.127.11.2303","article-title":"Hex is a transcriptional repressor that contributes to anterior identity and suppresses spemann organiser function","volume":"127","author":"Brickman","year":"2000","journal-title":"Development"},{"key":"2026041420241937700_stem2436-bib-0021","doi-asserted-by":"crossref","first-page":"2428","DOI":"10.1182\/blood-2003-02-0634","article-title":"The homeoprotein hex is required for hemangioblast differentiation","volume":"102","author":"Guo","year":"2003","journal-title":"Blood"},{"key":"2026041420241937700_stem2436-bib-0022","doi-asserted-by":"crossref","first-page":"2841","DOI":"10.1182\/blood.V79.11.2841.2841","article-title":"A diverged homeobox gene is involved in the proliferation and lineage commitment of human hematopoietic progenitors and highly expressed in acute myelogenous leukemia","volume":"79","author":"Deguchi","year":"1992","journal-title":"Blood"},{"key":"2026041420241937700_stem2436-bib-0023","doi-asserted-by":"crossref","first-page":"3242","DOI":"10.1182\/blood.V81.12.3242.3242","article-title":"Enforced expression of hlx homeobox gene prompts myeloid cell maturation and altered adherence properties of T cells","volume":"81","author":"Allen","year":"1993","journal-title":"Blood"},{"key":"2026041420241937700_stem2436-bib-0024","doi-asserted-by":"crossref","first-page":"2433","DOI":"10.1242\/dev.127.11.2433","article-title":"The homeobox gene hex is required in definitive endodermal tissues for normal forebrain, liver and thyroid formation","volume":"127","author":"Martinez Barbera","year":"2000","journal-title":"Development"},{"key":"2026041420241937700_stem2436-bib-0025","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1101\/gad.10.1.70","article-title":"Hlx homeo box gene is essential for an inductive tissue interaction that drives expansion of embryonic liver and gut","volume":"10","author":"Hentsch","year":"1996","journal-title":"Genes Dev"},{"key":"2026041420241937700_stem2436-bib-0026","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1038\/mt.2010.241","article-title":"Efficient generation of hepatoblasts from human ES cells and iPS cells by transient overexpression of homeobox gene HEX","volume":"19","author":"Inamura","year":"2011","journal-title":"Mol Ther"},{"key":"2026041420241937700_stem2436-bib-0027","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/j.ccr.2012.06.027","article-title":"H2.0-like homeobox regulates early hematopoiesis and promotes acute myeloid Leukemia","volume":"22","author":"Kawahara","year":"2012","journal-title":"Cancer Cell"},{"key":"2026041420241937700_stem2436-bib-0028","doi-asserted-by":"crossref","first-page":"D924","DOI":"10.1093\/nar\/gkr1188","article-title":"HGPD: Human gene and protein database, 2012 update","volume":"40","author":"Maruyama","year":"2012","journal-title":"Nucleic Acids Res"},{"key":"2026041420241937700_stem2436-bib-0029","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1016\/0092-8674(90)90385-R","article-title":"The Wnt-1 (int-1) proto-oncogene is required for development of a large region of the mouse brain","volume":"62","author":"McMahon","year":"1990","journal-title":"Cell"},{"key":"2026041420241937700_stem2436-bib-0030","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1038\/nmeth.1591","article-title":"A more efficient method to generate integration-free human iPS cells","volume":"8","author":"Okita","year":"2011","journal-title":"Nat Methods"},{"key":"2026041420241937700_stem2436-bib-0031","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1002\/stem.1293","article-title":"An efficient nonviral method to generate Integration-free Human-induced pluripotent stem cells from cord blood and peripheral blood Cells","volume":"31","author":"Okita","year":"2013","journal-title":"Stem Cells"},{"key":"2026041420241937700_stem2436-bib-0032","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1038\/sj.gt.3301206","article-title":"Plat-E: an efficient and stable system for transient packaging of retroviruses","volume":"7","author":"Morita","year":"2000","journal-title":"Gene Ther"},{"key":"2026041420241937700_stem2436-bib-0033","doi-asserted-by":"crossref","first-page":"12172","DOI":"10.1073\/pnas.1310291110","article-title":"Maturation, not initiation, is the major roadblock during reprogramming toward pluripotency from human fibroblasts","volume":"110","author":"Tanabe","year":"2013","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026041420241937700_stem2436-bib-0034","doi-asserted-by":"crossref","first-page":"e94735","DOI":"10.1371\/journal.pone.0094735","article-title":"Generation and characterization of induced pluripotent stem cells from Aid-deficient mice","volume":"9","author":"Shimamoto","year":"2014","journal-title":"PLoS One"},{"key":"2026041420241937700_stem2436-bib-0035","doi-asserted-by":"crossref","first-page":"e61540","DOI":"10.1371\/journal.pone.0061540","article-title":"Efficient and reproducible myogenic differentiation from human iPS cells: Prospects for modeling miyoshi myopathy in vitro","volume":"8","author":"Tanaka","year":"2013","journal-title":"PLoS One"},{"key":"2026041420241937700_stem2436-bib-0036","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/nprot.2008.211","article-title":"Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources","volume":"4","author":"Huang","year":"2008","journal-title":"Nat Protoc"},{"key":"2026041420241937700_stem2436-bib-0037","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1038\/nbt.1580","article-title":"Live cell imaging distinguishes bona fide human iPS cells from partially reprogrammed cells","volume":"27","author":"Chan","year":"2009","journal-title":"Nat Biotechnol"},{"key":"2026041420241937700_stem2436-bib-0038","doi-asserted-by":"crossref","first-page":"2017","DOI":"10.1089\/scd.2012.0651","article-title":"Zic3 enhances the generation of mouse induced pluripotent stem Cells","volume":"22","author":"Declercq","year":"2013","journal-title":"Stem Cells Dev"},{"key":"2026041420241937700_stem2436-bib-0039","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1016\/j.stem.2013.06.019","article-title":"Reprogramming of human fibroblasts to pluripotency with lineage Specifiers","volume":"13","author":"Montserrat","year":"2013","journal-title":"Cell Stem Cell"},{"key":"2026041420241937700_stem2436-bib-0040","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1016\/j.cell.2013.05.001","article-title":"Induction of pluripotency in mouse somatic cells with lineage Specifiers","volume":"153","author":"Shu","year":"2013","journal-title":"Cell"}],"container-title":["Stem Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fstem.2436","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fstem.2436","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/stem.2436","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/stem.2436","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/am-pdf\/10.1002\/stem.2436","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/stmcls\/article-pdf\/34\/11\/2661\/42026913\/stmcls_34_11_2661.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/stmcls\/article-pdf\/34\/11\/2661\/42026913\/stmcls_34_11_2661.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T00:47:47Z","timestamp":1776214067000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/stmcls\/article\/34\/11\/2661\/6408392"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,7,8]]},"references-count":40,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2016,11,1]]}},"URL":"https:\/\/doi.org\/10.1002\/stem.2436","relation":{},"ISSN":["1066-5099","1549-4918"],"issn-type":[{"value":"1066-5099","type":"print"},{"value":"1549-4918","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2016,11,1]]},"published":{"date-parts":[[2016,7,8]]}}}