{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T02:51:53Z","timestamp":1790823113915,"version":"4.1.0"},"reference-count":40,"publisher":"Springer Science and Business Media LLC","issue":"10","license":[{"start":{"date-parts":[[2017,8,28]],"date-time":"2017-08-28T00:00:00Z","timestamp":1503878400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"},{"start":{"date-parts":[[2017,8,28]],"date-time":"2017-08-28T00:00:00Z","timestamp":1503878400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Genet"],"published-print":{"date-parts":[[2017,10,1]]},"DOI":"10.1038\/ng.3939","type":"journal-article","created":{"date-parts":[[2017,8,28]],"date-time":"2017-08-28T15:05:22Z","timestamp":1503932722000},"page":"1539-1545","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":131,"title":["Composition and dosage of a multipartite enhancer cluster control developmental expression of Ihh (Indian hedgehog)"],"prefix":"10.1038","volume":"49","author":[{"given":"Anja J","family":"Will","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Cova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1969-2313","authenticated-orcid":false,"given":"Marco","family":"Osterwalder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wing-Lee","family":"Chan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Wittler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norbert","family":"Brieske","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Verena","family":"Heinrich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Pierre","family":"de Villartay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1765-4241","authenticated-orcid":false,"given":"Martin","family":"Vingron","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Klopocki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4130-7784","authenticated-orcid":false,"given":"Axel","family":"Visel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3165-036X","authenticated-orcid":false,"given":"Dar\u00edo G","family":"Lupi\u00e1\u00f1ez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9788-3166","authenticated-orcid":false,"given":"Stefan","family":"Mundlos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,8,28]]},"reference":[{"key":"BFng3939_CR1","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1002\/ajmg.a.36811","volume":"167A","author":"E Barroso","year":"2015","unstructured":"Barroso, E. et al. Identification of the fourth duplication of upstream IHH regulatory elements, in a family with craniosynostosis Philadelphia type, helps to define the phenotypic characterization of these regulatory elements. Am. J. Med. Genet. A. 167A, 902\u2013906 (2015).","journal-title":"Am. J. Med. Genet. A."},{"key":"BFng3939_CR2","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.ajhg.2010.11.006","volume":"88","author":"E Klopocki","year":"2011","unstructured":"Klopocki, E. et al. Copy-number variations involving the IHH locus are associated with syndactyly and craniosynostosis. Am. J. Hum. Genet. 88, 70\u201375 (2011).","journal-title":"Am. J. Hum. Genet."},{"key":"BFng3939_CR3","doi-asserted-by":"crossref","unstructured":"ENCODE Project Consortium. The ENCODE (ENCyclopedia Of DNA Elements) Project. Science 306, 636\u2013640 (2004).","DOI":"10.1126\/science.1105136"},{"key":"BFng3939_CR4","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1038\/nature12787","volume":"507","author":"R Andersson","year":"2014","unstructured":"Andersson, R. et al. An atlas of active enhancers across human cell types and tissues. Nature 507, 455\u2013461 (2014).","journal-title":"Nature"},{"key":"BFng3939_CR5","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1038\/nbt1010-1045","volume":"28","author":"BE Bernstein","year":"2010","unstructured":"Bernstein, B.E. et al. The NIH Roadmap Epigenomics Mapping Consortium. Nat. Biotechnol. 28, 1045\u20131048 (2010).","journal-title":"Nat. Biotechnol."},{"key":"BFng3939_CR6","doi-asserted-by":"crossref","first-page":"1314","DOI":"10.1126\/science.1160631","volume":"321","author":"JW Hong","year":"2008","unstructured":"Hong, J.W., Hendrix, D.A. & Levine, M.S. Shadow enhancers as a source of evolutionary novelty. Science 321, 1314 (2008).","journal-title":"Science"},{"key":"BFng3939_CR7","doi-asserted-by":"crossref","first-page":"1562","DOI":"10.1016\/j.cub.2010.07.043","volume":"20","author":"MW Perry","year":"2010","unstructured":"Perry, M.W., Boettiger, A.N., Bothma, J.P. & Levine, M. Shadow enhancers foster robustness of Drosophila gastrulation. Curr. Biol. 20, 1562\u20131567 (2010).","journal-title":"Curr. Biol."},{"key":"BFng3939_CR8","doi-asserted-by":"crossref","first-page":"4075","DOI":"10.1242\/dev.069146","volume":"138","author":"L Dunipace","year":"2011","unstructured":"Dunipace, L., Ozdemir, A. & Stathopoulos, A. Complex interactions between cis-regulatory modules in native conformation are critical for Drosophilasnail expression. Development 138, 4075\u20134084 (2011).","journal-title":"Development"},{"key":"BFng3939_CR9","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.cub.2015.11.034","volume":"26","author":"E Cannav\u00f2","year":"2016","unstructured":"Cannav\u00f2, E. et al. Shadow enhancers are pervasive features of developmental regulatory networks. Curr. Biol. 26, 38\u201351 (2016).","journal-title":"Curr. Biol."},{"key":"BFng3939_CR10","doi-asserted-by":"crossref","first-page":"2247","DOI":"10.1016\/j.cub.2012.09.051","volume":"22","author":"MW Perry","year":"2012","unstructured":"Perry, M.W., Bothma, J.P., Luu, R.D. & Levine, M. Precision of hunchback expression in the Drosophila embryo. Curr. Biol. 22, 2247\u20132252 (2012).","journal-title":"Curr. Biol."},{"key":"BFng3939_CR11","doi-asserted-by":"crossref","first-page":"2072","DOI":"10.1101\/gad.13.16.2072","volume":"13","author":"B St-Jacques","year":"1999","unstructured":"St-Jacques, B., Hammerschmidt, M. & McMahon, A.P. Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation. Genes Dev. 13, 2072\u20132086 (1999).","journal-title":"Genes Dev."},{"key":"BFng3939_CR12","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1101\/gr.213066.116","volume":"27","author":"G Andrey","year":"2017","unstructured":"Andrey, G. et al. Characterization of hundreds of regulatory landscapes in developing limbs reveals two regimes of chromatin folding. Genome Res. 27, 223\u2013233 (2017).","journal-title":"Genome Res."},{"key":"BFng3939_CR13","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1016\/j.cell.2015.07.038","volume":"162","author":"Y Guo","year":"2015","unstructured":"Guo, Y. et al. CRISPR inversion of CTCF sites alters genome topology and enhancer\/promoter function. Cell 162, 900\u2013910 (2015).","journal-title":"Cell"},{"key":"BFng3939_CR14","doi-asserted-by":"crossref","first-page":"1665","DOI":"10.1016\/j.cell.2014.11.021","volume":"159","author":"SS Rao","year":"2014","unstructured":"Rao, S.S. et al. A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell 159, 1665\u20131680 (2014).","journal-title":"Cell"},{"key":"BFng3939_CR15","first-page":"E6456","volume":"112","author":"AL Sanborn","year":"2015","unstructured":"Sanborn, A.L. et al. Chromatin extrusion explains key features of loop and domain formation in wild-type and engineered genomes. Proc. Natl. Acad. Sci. USA 112, E6456\u2013E6465 (2015).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"BFng3939_CR16","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1016\/j.celrep.2015.02.004","volume":"10","author":"M Vietri Rudan","year":"2015","unstructured":"Vietri Rudan, M. et al. Comparative Hi-C reveals that CTCF underlies evolution of chromosomal domain architecture. Cell Reports 10, 1297\u20131309 (2015).","journal-title":"Cell Reports"},{"key":"BFng3939_CR17","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1038\/ng.790","volume":"43","author":"S Ruf","year":"2011","unstructured":"Ruf, S. et al. Large-scale analysis of the regulatory architecture of the mouse genome with a transposon-associated sensor. Nat. Genet. 43, 379\u2013386 (2011).","journal-title":"Nat. Genet."},{"key":"BFng3939_CR18","doi-asserted-by":"crossref","first-page":"21931","DOI":"10.1073\/pnas.1016071107","volume":"107","author":"MP Creyghton","year":"2010","unstructured":"Creyghton, M.P. et al. Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc. Natl. Acad. Sci. USA 107, 21931\u201321936 (2010).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"BFng3939_CR19","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1101\/gr.097857.109","volume":"20","author":"KS Pollard","year":"2010","unstructured":"Pollard, K.S., Hubisz, M.J., Rosenbloom, K.R. & Siepel, A. Detection of nonneutral substitution rates on mammalian phylogenies. Genome Res. 20, 110\u2013121 (2010).","journal-title":"Genome Res."},{"key":"BFng3939_CR20","doi-asserted-by":"crossref","first-page":"D88","DOI":"10.1093\/nar\/gkl822","volume":"35","author":"A Visel","year":"2007","unstructured":"Visel, A., Minovitsky, S., Dubchak, I. & Pennacchio, L.A. VISTA Enhancer Browser\u2014a database of tissue-specific human enhancers. Nucleic Acids Res. 35, D88\u2013D92 (2007).","journal-title":"Nucleic Acids Res."},{"key":"BFng3939_CR21","doi-asserted-by":"publisher","unstructured":"Kraft, K. et al. Deletions, inversions, duplications: engineering of structural variants using CRISPR\/Cas in mice. Cell Rep. http:\/\/dx.doi.org\/10.1016\/j.celrep.2015.01.016 (2015).","DOI":"10.1016\/j.celrep.2015.01.016"},{"key":"BFng3939_CR22","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/j.cell.2005.12.030","volume":"124","author":"D Buck","year":"2006","unstructured":"Buck, D. et al. Cernunnos, a novel nonhomologous end-joining factor, is mutated in human immunodeficiency with microcephaly. Cell 124, 287\u2013299 (2006).","journal-title":"Cell"},{"key":"BFng3939_CR23","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1016\/j.molcel.2008.07.017","volume":"31","author":"G Li","year":"2008","unstructured":"Li, G. et al. Lymphocyte-specific compensation for XLF\/cernunnos end-joining functions in V(D)J recombination. Mol. Cell 31, 631\u2013640 (2008).","journal-title":"Mol. Cell"},{"key":"BFng3939_CR24","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1128\/MCB.01057-12","volume":"33","author":"G Vera","year":"2013","unstructured":"Vera, G. et al. Cernunnos deficiency reduces thymocyte life span and alters the T cell repertoire in mice and humans. Mol. Cell. Biol. 33, 701\u2013711 (2013).","journal-title":"Mol. Cell. Biol."},{"key":"BFng3939_CR25","doi-asserted-by":"crossref","first-page":"3669","DOI":"10.1242\/dev.041954","volume":"136","author":"R Hern\u00e1ndez-Mart\u00ednez","year":"2009","unstructured":"Hern\u00e1ndez-Mart\u00ednez, R., Castro-Obreg\u00f3n, S. & Covarrubias, L. Progressive interdigital cell death: regulation by the antagonistic interaction between fibroblast growth factor 8 and retinoic acid. Development 136, 3669\u20133678 (2009).","journal-title":"Development"},{"key":"BFng3939_CR26","doi-asserted-by":"crossref","first-page":"14211","DOI":"10.1073\/pnas.1009314107","volume":"107","author":"F Witte","year":"2010","unstructured":"Witte, F., Chan, D., Economides, A.N., Mundlos, S. & Stricker, S. Receptor tyrosine kinase\u2013like orphan receptor 2 (ROR2) and Indian hedgehog regulate digit outgrowth mediated by the phalanx-forming region. Proc. Natl. Acad. Sci. USA 107, 14211\u201314216 (2010).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"BFng3939_CR27","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1016\/j.tig.2012.03.012","volume":"28","author":"E Anderson","year":"2012","unstructured":"Anderson, E., Peluso, S., Lettice, L.A. & Hill, R.E. Human limb abnormalities caused by disruption of hedgehog signaling. Trends Genet. 28, 364\u2013373 (2012).","journal-title":"Trends Genet."},{"key":"BFng3939_CR28","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1111\/j.1440-169X.2007.00943.x","volume":"49","author":"RE Hill","year":"2007","unstructured":"Hill, R.E. How to make a zone of polarizing activity: insights into limb development via the abnormality preaxial polydactyly. Dev. Growth Differ. 49, 439\u2013448 (2007).","journal-title":"Dev. Growth Differ."},{"key":"BFng3939_CR29","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1038\/ng.3605","volume":"48","author":"D Hay","year":"2016","unstructured":"Hay, D. et al. Genetic dissection of the \u03b1-globin super-enhancer in vivo. Nat. Genet. 48, 895\u2013903 (2016).","journal-title":"Nat. Genet."},{"key":"BFng3939_CR30","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1038\/ng.3606","volume":"48","author":"HY Shin","year":"2016","unstructured":"Shin, H.Y. et al. Hierarchy within the mammary STAT5-driven Wap super-enhancer. Nat. Genet. 48, 904\u2013911 (2016).","journal-title":"Nat. Genet."},{"key":"BFng3939_CR31","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1016\/j.devcel.2013.01.025","volume":"24","author":"M Marini\u0107\u00b4","year":"2013","unstructured":"Marini\u0107\u00b4, M., Aktas, T., Ruf, S. & Spitz, F. An integrated holo-enhancer unit defines tissue and gene specificity of the Fgf8 regulatory landscape. Dev. Cell 24, 530\u2013542 (2013).","journal-title":"Dev. Cell"},{"key":"BFng3939_CR32","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1016\/j.cell.2011.10.023","volume":"147","author":"T Montavon","year":"2011","unstructured":"Montavon, T. et al. A regulatory archipelago controls Hox genes transcription in digits. Cell 147, 1132\u20131145 (2011).","journal-title":"Cell"},{"key":"BFng3939_CR33","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1038\/nature19800","volume":"538","author":"M Franke","year":"2016","unstructured":"Franke, M. et al. Formation of new chromatin domains determines pathogenicity of genomic duplications. Nature 538, 265\u2013269 (2016).","journal-title":"Nature"},{"key":"BFng3939_CR34","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1016\/j.cell.2015.04.004","volume":"161","author":"DG Lupi\u00e1\u00f1ez","year":"2015","unstructured":"Lupi\u00e1\u00f1ez, D.G. et al. Disruptions of topological chromatin domains cause pathogenic rewiring of gene\u2013enhancer interactions. Cell 161, 1012\u20131025 (2015).","journal-title":"Cell"},{"key":"BFng3939_CR35","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1007\/978-1-60761-974-1_3","volume":"693","author":"J Artus","year":"2011","unstructured":"Artus, J. & Hadjantonakis, A.K. Generation of chimeras by aggregation of embryonic stem cells with diploid or tetraploid mouse embryos. Methods Mol. Biol. 693, 37\u201356 (2011).","journal-title":"Methods Mol. Biol."},{"key":"BFng3939_CR36","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1038\/326292a0","volume":"326","author":"M Hooper","year":"1987","unstructured":"Hooper, M., Hardy, K., Handyside, A., Hunter, S. & Monk, M. HPRT-deficient (Lesch\u2013Nyhan) mouse embryos derived from germline colonization by cultured cells. Nature 326, 292\u2013295 (1987).","journal-title":"Nature"},{"key":"BFng3939_CR37","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/B978-0-12-391938-0.00004-5","volume":"513","author":"HJ van de Werken","year":"2012","unstructured":"van de Werken, H.J. et al. 4C technology: protocols and data analysis. Methods Enzymol. 513, 89\u2013112 (2012).","journal-title":"Methods Enzymol."},{"key":"BFng3939_CR38","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1093\/bioinformatics\/btp324","volume":"25","author":"H Li","year":"2009","unstructured":"Li, H. & Durbin, R. Fast and accurate short read alignment with Burrows\u2013Wheeler transform. Bioinformatics 25, 1754\u20131760 (2009).","journal-title":"Bioinformatics"},{"key":"BFng3939_CR39","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1093\/bioinformatics\/btr064","volume":"27","author":"CE Grant","year":"2011","unstructured":"Grant, C.E., Bailey, T.L. & Noble, W.S. FIMO: scanning for occurrences of a given motif. Bioinformatics 27, 1017\u20131018 (2011).","journal-title":"Bioinformatics"},{"key":"BFng3939_CR40","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1016\/j.cell.2007.05.009","volume":"129","author":"A Barski","year":"2007","unstructured":"Barski, A. et al. High-resolution profiling of histone methylations in the human genome. Cell 129, 823\u2013837 (2007).","journal-title":"Cell"}],"container-title":["Nature Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/ng.3939.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/ng.3939","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/www.nature.com\/doifinder\/10.1038\/ng.3939","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"},{"URL":"https:\/\/www.nature.com\/articles\/ng.3939.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,17]],"date-time":"2025-02-17T00:57:34Z","timestamp":1739753854000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/ng.3939"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,8,28]]},"references-count":40,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2017,10,1]]}},"alternative-id":["BFng3939"],"URL":"https:\/\/doi.org\/10.1038\/ng.3939","relation":{},"ISSN":["1061-4036","1546-1718"],"issn-type":[{"value":"1061-4036","type":"print"},{"value":"1546-1718","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,8,28]]},"assertion":[{"value":"21 February 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 July 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 August 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}