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To understand this paradox, we focus on TCOF1, a broadly expressed regulator of rRNA synthesis, whose haploinsufficiency causes Treacher Collins syndrome (TCS). We show that transitional cranial neural crest cells (tCNCC) undergoing mesenchymal specification exhibit extreme dosage-sensitivity to TCOF1, but not to RNA polymerase I, explaining both cellular origins of TCS and prevalence of TCOF1 mutations in the disease. To maintain robust expression, TCOF1 deploys CNCC-specific enhancers that buffer against fluctuations in promoter-regulating factors, converting sensitive expression responses into threshold-protected outputs. Systematic promoter-enhancer coupling experiments demonstrate this principle generalizes across many dosage-sensitive housekeeping genes, whose promoters operate near saturation and only reveal their enhancer-dependency under suboptimal conditions. Thus, enhancers play a unique role at housekeeping promoters: rather than amplifying expression, they ensure its robustness during vulnerable developmental transitions.<\/jats:p>","DOI":"10.64898\/2026.07.29.741571","type":"posted-content","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:35:12Z","timestamp":1785404112000},"source":"Crossref","is-referenced-by-count":2,"title":["Enhancer buffering protects dosage-sensitive housekeeping genes during vulnerable developmental transitions"],"prefix":"10.64898","author":[{"given":"Chunyang","family":"Ni","sequence":"first","affiliation":[{"name":"Department of Chemical and Systems Biology, Stanford University School of Medicine; Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia","family":"Ichino","sequence":"additional","affiliation":[{"name":"Department of Chemical and Systems Biology, Stanford University School of Medicine; Stanford, CA 94305, USA"},{"name":"Howard Hughes Medical Institute, Stanford University School of Medicine; Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomek","family":"Swigut","sequence":"additional","affiliation":[{"name":"Department of Chemical and Systems Biology, Stanford University School of Medicine; Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna","family":"Wysocka","sequence":"additional","affiliation":[{"name":"Department of Chemical and Systems Biology, Stanford University School of Medicine; Stanford, CA 94305, USA"},{"name":"Department of Developmental Biology, Stanford University School of Medicine; Stanford, CA 94305, USA"},{"name":"Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine; Stanford, CA 94305, USA"},{"name":"Howard Hughes Medical Institute, Stanford University School of Medicine; Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026090308401238000_2026.07.29.741571v2.1","doi-asserted-by":"crossref","unstructured":"M. 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