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Reconciling such observations requires quantitative studies of TF dosage effects at trait-relevant ranges, largely lacking so far. TFs play central roles in both normal-range and disease-associated variation in craniofacial morphology; we therefore developed an approach to precisely modulate TF levels in human facial progenitor cells and applied it to SOX9, a TF associated with craniofacial variation and disease (Pierre Robin sequence (PRS)). Most SOX9-dependent regulatory elements (REs) are buffered against small decreases in SOX9 dosage, but REs directly and primarily regulated by SOX9 show heightened sensitivity to SOX9 dosage; these RE responses partially predict gene expression responses. Sensitive REs and genes preferentially affect functional chondrogenesis and PRS-like craniofacial shape variation. We propose that such REs and genes underlie the sensitivity of specific phenotypes to TF dosage, while buffering of other genes leads to robust, nonlinear dosage-to-phenotype relationships.<\/jats:p>","DOI":"10.1038\/s41588-023-01366-2","type":"journal-article","created":{"date-parts":[[2023,4,6]],"date-time":"2023-04-06T12:02:59Z","timestamp":1680782579000},"page":"841-851","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":154,"title":["Precise modulation of transcription factor levels identifies features underlying dosage sensitivity"],"prefix":"10.1038","volume":"55","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2635-7967","authenticated-orcid":false,"given":"Sahin","family":"Naqvi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seungsoo","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanne","family":"Hoskens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harold S.","family":"Matthews","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8325-0026","authenticated-orcid":false,"given":"Richard A.","family":"Spritz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6254-7082","authenticated-orcid":false,"given":"Ophir D.","family":"Klein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7192-9103","authenticated-orcid":false,"given":"Benedikt","family":"Hallgr\u00edmsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomek","family":"Swigut","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9489-9819","authenticated-orcid":false,"given":"Peter","family":"Claes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8828-5236","authenticated-orcid":false,"given":"Jonathan K.","family":"Pritchard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6909-6544","authenticated-orcid":false,"given":"Joanna","family":"Wysocka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,4,6]]},"reference":[{"key":"1366_CR1","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1038\/nrg3207","volume":"13","author":"F Spitz","year":"2012","unstructured":"Spitz, F. & Furlong, E. 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