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Identification of functional non-coding variants associated with orofacial cleft.

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Τίτλος: Identification of functional non-coding variants associated with orofacial cleft.
Συγγραφείς: Kumari P; Department of Oral Health Sciences, University of Washington, Seattle, WA, USA., Friedman RZ; Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.; The Edison Family Center for Genome Sciences & Systems Biology, Washington University School of Medicine, St. Louis, MO, USA., Curtis SW; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA., Pi L; Cencora-PharmaLex, Conshohocken, PA, USA., Paraiso K; Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA., Visel A; Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.; U.S. Department of Energy Joint Genome Institute, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.; School of Natural Sciences, University of California, Merced, CA, USA., Rhea L; Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA., Dunnwald M; Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA., Patni AP; Department of Oral Health Sciences, University of Washington, Seattle, WA, USA.; Department of Biochemistry, University of Washington School of Medicine, Seattle, WA, USA.; Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA, USA., Mar D; Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA, USA.; UW Medicine South Lake Union, University of Washington, Seattle, WA, USA., Bomsztyk K; Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA, USA.; UW Medicine South Lake Union, University of Washington, Seattle, WA, USA.; Matchstick Technologies, Inc, Kirkland, WA, USA., Mathieu J; Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA, USA.; Department of Comparative Medicine, University of Washington School of Medicine, Seattle, WA, USA., Ruohola-Baker H; Department of Oral Health Sciences, University of Washington, Seattle, WA, USA.; Department of Biochemistry, University of Washington School of Medicine, Seattle, WA, USA.; Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA, USA.; Brotman Baty Institute for Precision Medicine, Seattle, WA, USA.; Department of Bioengineering, University of Washington, Seattle, WA, USA.; Institute on Human Development and Disability, University of Washington, Seattle, WA, USA., Leslie-Clarkson EJ; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA., White MA; Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.; The Edison Family Center for Genome Sciences & Systems Biology, Washington University School of Medicine, St. Louis, MO, USA., Cohen BA; Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.; The Edison Family Center for Genome Sciences & Systems Biology, Washington University School of Medicine, St. Louis, MO, USA., Cornell RA; Department of Oral Health Sciences, University of Washington, Seattle, WA, USA. cornellr@uw.edu.; Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA, USA. cornellr@uw.edu.; Institute on Human Development and Disability, University of Washington, Seattle, WA, USA. cornellr@uw.edu.
Πηγή: Nature communications [Nat Commun] 2025 Jul 16; Vol. 16 (1), pp. 6545. Date of Electronic Publication: 2025 Jul 16.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
Imprint Name(s): Original Publication: [London] : Nature Pub. Group
Ιατρικοί όροι (MeSH): Cleft Palate*/genetics , Cleft Lip*/genetics , Polymorphism, Single Nucleotide*, Interferon Regulatory Factors/genetics ; Interferon Regulatory Factors/metabolism ; Forkhead Transcription Factors/genetics ; Forkhead Transcription Factors/metabolism ; Transcription Factor AP-2/genetics ; Induced Pluripotent Stem Cells/metabolism ; Humans ; Genome-Wide Association Study ; Genetic Predisposition to Disease ; Alleles ; Cell Line ; Enhancer Elements, Genetic
Περίληψη: Oral facial cleft (OFC) comprises cleft lip with or without cleft palate (CL/P) or cleft palate only. Genome wide association studies (GWAS) of isolated OFC have identified common single nucleotide polymorphisms (SNPs) in many genomic loci where the presumed effector gene (for example, IRF6 in the 1q32 locus) is expressed in embryonic oral epithelium. To identify candidates for functional SNPs at eight such loci we conduct a massively parallel reporter assay in a fetal oral epithelial cell line, revealing SNPs with allele-specific effects on enhancer activity. We filter these SNPs against chromatin-mark evidence of enhancers and test a subset in traditional reporter assays, which support the candidacy of SNPs at loci containing FOXE1, IRF6,  MAFB, TFAP2A, and TP63. For two SNPs near IRF6 and one near FOXE1, we engineer the genome of induced pluripotent stem cells, differentiate the cells into embryonic oral epithelium, and discover allele-specific effects on the levels of effector gene expression, and, in two cases, the binding affinity of transcription factors FOXE1 or ETS2. Conditional analyses of GWAS data suggest the two functional SNPs near IRF6 account for the majority of risk for CL/P at this locus. This study connects genetic variation associated with OFC to mechanisms of pathogenesis.
(© 2025. The Author(s).)
Competing Interests: Competing interests: L.P. is an employee of Cencora-PharmaLex. K.B. is co-founder of Matchstick Technologies, Inc., and co-inventor of PIXUL, used here for chromatin immunoprecipitation experiments. The remaining authors declare no competing interests.
Σχόλια: Update of: bioRxiv. 2025 Feb 25:2024.06.01.596914. doi: 10.1101/2024.06.01.596914.. (PMID: 40027800)
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Grant Information: R01 AR067739 United States AR NIAMS NIH HHS; DE027362 U.S. Department of Health & Human Services | NIH | National Institute of Dental and Craniofacial Research (NIDCR); R42 HG010855 United States HG NHGRI NIH HHS; U01 CA246503 United States CA NCI NIH HHS; P30 DK017047 United States DK NIDDK NIH HHS; R01 DE028599 United States DE NIDCR NIH HHS; R01 DE033016 United States DE NIDCR NIH HHS; F31 HG011431 United States HG NHGRI NIH HHS; R01 DE027362 United States DE NIDCR NIH HHS
Substance Nomenclature: 0 (Interferon Regulatory Factors)
0 (Forkhead Transcription Factors)
0 (IRF6 protein, human)
0 (FOXE1 protein, human)
0 (Transcription Factor AP-2)
0 (TFAP2A protein, human)
Entry Date(s): Date Created: 20250716 Date Completed: 20250716 Latest Revision: 20250905
Update Code: 20260130
PubMed Central ID: PMC12267437
DOI: 10.1038/s41467-025-61734-w
PMID: 40670354
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:2041-1723
DOI:10.1038/s41467-025-61734-w