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

  1. Huan Liu  Is a corresponding author
  2. Kaylia Duncan
  3. Annika Helverson
  4. Priyanka Kumari
  5. Camille Mumm
  6. Yao Xiao
  7. Jenna Colavincenzo Carlson
  8. Fabrice Darbellay
  9. Axel Visel
  10. Elizabeth Leslie
  11. Patrick Breheny
  12. Albert J Erives
  13. Robert A Cornell  Is a corresponding author
  1. Wuhan University, China
  2. University of Iowa, United States
  3. University of Pittsburgh, United States
  4. Lawrence Berkeley Laboratories, United States
  5. DOE Joint Genome Institute, United States
  6. Emory University School of Medicine, United States

Abstract

Genome wide association studies for non-syndromic orofacial cleft (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 effect 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.

Data availability

1 Raw and processed sequencing data were deposited in GEO repository (GSE140241, GSE139945 and GSE139809).2 Custom scripts and piplines we deployed for sequencing data analysis and visualization are available at https://github.com/Badgerliu/periderm_ATACSeq.3 All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Huan Liu

    State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory for Oral Biomedicine of Ministry of Education (KLOBM), School and Hospital of Stomatology, Wuhan University, Wuhan, China
    For correspondence
    liu.huan@whu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9947-6687
  2. Kaylia Duncan

    College of Medicine, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Annika Helverson

    College of Medicine, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Priyanka Kumari

    College of Medicine, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Camille Mumm

    College of Medicine, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Yao Xiao

    State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory for Oral Biomedicine of Ministry of Education (KLOBM), School and Hospital of Stomatology, Wuhan University, Wuhan, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Jenna Colavincenzo Carlson

    Department of Biostatistics, University of Pittsburgh, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5483-0833
  8. Fabrice Darbellay

    Environmental Genomics and Systems Biology Division, Lawrence Berkeley Laboratories, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Axel Visel

    DOE Joint Genome Institute, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4130-7784
  10. Elizabeth Leslie

    Department of Human Genetics, Emory University School of Medicine, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Patrick Breheny

    Department of Biostatistics, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0650-1119
  12. Albert J Erives

    Department of Biology, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7107-5518
  13. Robert A Cornell

    College of Medicine, University of Iowa, Iowa City, United States
    For correspondence
    robert-cornell@uiowa.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4207-9100

Funding

National Institutes of Health (DE023575)

  • Robert A Cornell

National Institute for Health Research (DE027362)

  • Robert A Cornell

National Institute of Dental and Craniofacial Research (DE025060)

  • Elizabeth Leslie

National Institute of Dental and Craniofacial Research (DE024427)

  • Axel Visel

National Institute of Dental and Craniofacial Research (DE028599)

  • Axel Visel

National Natural Science Foundation of China (81771057)

  • Huan Liu

National Natural Science Foundation of China (81400477)

  • Huan Liu

Natural Science Foundation of Hubei Province (2017CFB515)

  • Huan Liu

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: D. rerio were maintained in the University of Iowa Animal Care Facility according to a standard protocol (protocol no. 6011616). All mouse experiments were performed in accordance with approval of the Institutional Animal Care and Use Committees at the School and Hospital of Stomatology of Wuhan University (protocol no. 00271454).Mouse experiments for LacZ reporter transgenic animal work performed at the Lawrence Berkeley National Laboratory (LBNL) were reviewed and approved by the LBNL Animal Welfare and Research Committee.

Reviewing Editor

  1. Marianne E Bronner, California Institute of Technology, United States

Publication history

  1. Received: August 25, 2019
  2. Accepted: February 6, 2020
  3. Accepted Manuscript published: February 7, 2020 (version 1)
  4. Version of Record published: February 24, 2020 (version 2)

Copyright

© 2020, Liu et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Huan Liu
  2. Kaylia Duncan
  3. Annika Helverson
  4. Priyanka Kumari
  5. Camille Mumm
  6. Yao Xiao
  7. Jenna Colavincenzo Carlson
  8. Fabrice Darbellay
  9. Axel Visel
  10. Elizabeth Leslie
  11. Patrick Breheny
  12. Albert J Erives
  13. Robert A Cornell
(2020)
Analysis of zebrafish periderm enhancers facilitates identification of a regulatory variant near human KRT8/18
eLife 9:e51325.
https://doi.org/10.7554/eLife.51325

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