Analysis of zebrafish periderm enhancers facilitates identification of a regulatory variant near human KRT8/18

• Type of Material: Article
• Authors: Huan Liu, Wuhan University; Kaylia Duncan, University of Iowa; Annika Helverson, University of Iowa; Priyanka Kumari, University of Iowa; Camille Mumm, University of Iowa; Yao Xiao, Wuhan University; Jenna Colavincenzo Carlson, University of Pittsburgh; Fabrice Darbellay, Lawrence Berkeley Labs; Axel Visel, Lawrence Berkeley Labs; Elizabeth Leslie, Emory University; Patrick Breheny, University of Iowa; Albert J. Erives, University of Iowa; Robert A. Cornell, University of Iowa
• Language: English
• Date: 2020-02-07
• Publisher: ELIFE SCIENCES PUBLICATIONS LTD
• Publication Version: Final Published Version
• Copyright Statement: © Liu et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.7554/eLife.51325
• Title of Journal or Parent Work: ELIFE
• Volume: 9
• Grant/Funding Information: This work supported by grants from the NIH including DE023575 (RAC), DE027362 (RAC), DE025060 (EJL), DE024427 (AV), DE028599 (AV), and NCI P30CA086862 (University of Iowa Flow Cytometry Facility), from the National Natural Science Foundation of China (NO. 81771057; 81400477) (HL), the Natural Science Foundation of Hubei Province (NO. 2017CFB515) (HL) and the Young Elite Scientist Sponsorship Program by CAST (NO. 2017QNRC001) (HL).; Research at Lawrence Berkeley National Laboratory was performed under Department of Energy Contract DE-AC02-05CH11231, University of California.; The numerical calculations in this paper have been done on the supercomputing system in the Supercomputing Center of Wuhan University and at the High Performance Computing Cluster at the University of Iowa.
• Keywords: Life Sciences & Biomedicine - Other Topics; CLEFT-LIP; MEDIATED TRANSGENESIS; Life Sciences & Biomedicine; ORAL EPITHELIUM; CHROMATIN; BINDING; Biology; DIFFERENTIATION; EXPRESSION; Science & Technology; IRF6; PALATE; RNA-SEQ
• Research Categories: Biology, Genetics

Abstract

Genome-wide association studies for non-syndromic orofacial clefting (OFC) have identified single nucleotide polymorphisms (SNPs) at loci where the presumed risk-relevant gene is expressed in oral periderm. The functional subsets of such SNPs are difficult to predict because the sequence underpinnings of periderm enhancers are unknown. We applied ATAC-seq to models of human palate periderm, including zebrafish periderm, mouse embryonic palate epithelia, and a human oral epithelium cell line, and to complementary mesenchymal cell types. We identified sets of enhancers specific to the epithelial cells and trained gapped-kmer support-vector-machine classifiers on these sets. We used the classifiers to predict the effects of 14 OFC-associated SNPs at 12q13 near KRT18. All the classifiers picked the same SNP as having the strongest effect, but the significance was highest with the classifier trained on zebrafish periderm. Reporter and deletion analyses support this SNP as lying within a periderm enhancer regulating KRT18/KRT8 expression.