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Disease-linked regulatory DNA variants and homeostatic transcription factors in epidermis

Author

Listed:
  • Douglas F. Porter

    (Stanford University School of Medicine)

  • Robin M. Meyers

    (Stanford University School of Medicine
    Stanford University School of Medicine)

  • Weili Miao

    (Stanford University School of Medicine)

  • David L. Reynolds

    (Stanford University School of Medicine)

  • Audrey W. Hong

    (Stanford University School of Medicine)

  • Xue Yang

    (Stanford University School of Medicine
    Stanford University School of Medicine)

  • Suhas Srinivasan

    (Stanford University School of Medicine)

  • Smarajit Mondal

    (Stanford University School of Medicine)

  • Zurab Siprashvili

    (Stanford University School of Medicine)

  • Tania Fabo

    (Stanford University School of Medicine)

  • Ronghao Zhou

    (Stanford University School of Medicine
    Lucile Packard Children’s Hospital)

  • Tri Nguyen

    (Stanford University School of Medicine
    Lucile Packard Children’s Hospital)

  • Luca Ducoli

    (Stanford University School of Medicine)

  • Jordan M. Meyers

    (Stanford University School of Medicine)

  • Duy T. Nguyen

    (Stanford University School of Medicine)

  • Lisa A. Ko

    (Stanford University School of Medicine)

  • Laura N. Kellman

    (Stanford University School of Medicine
    Stanford University School of Medicine)

  • Ibtihal Elfaki

    (Stanford University School of Medicine)

  • Margaret Guo

    (Stanford University School of Medicine
    Stanford University)

  • Mårten CG Winge

    (Stanford University School of Medicine)

  • Leandra V. Jackrazi

    (Stanford University School of Medicine)

  • Vanessa Lopez-Pajares

    (Stanford University School of Medicine)

  • Betty B. Liu

    (Stanford University School of Medicine)

  • Yuanhao Qu

    (Stanford University School of Medicine)

  • Imani E. Porter

    (Stanford University School of Medicine
    Hampton University)

  • Samuel H. Kim

    (Stanford University School of Medicine)

  • Gyuhyeon Kim

    (Stanford University School of Medicine
    Stanford University School of Medicine)

  • Shiying Tao

    (Stanford University School of Medicine)

  • Jesse M. Engreitz

    (Stanford University School of Medicine
    Lucile Packard Children’s Hospital
    Stanford University School of Medicine
    Broad Institute of MIT and Harvard)

  • Paul A. Khavari

    (Stanford University School of Medicine
    Stanford University School of Medicine
    Veterans Affairs Palo Alto Healthcare System)

Abstract

Identifying noncoding single nucleotide variants (SNVs) in regulatory DNA linked to polygenic disease risk, the transcription factors (TFs) they bind, and the genes they dysregulate is a goal in polygenic disease research. Here, we use massively parallel reporter analysis of 3451 SNVs linked to risk for polygenic skin diseases with disrupted epidermal homeostasis to identify 355 differentially active SNVs (daSNVs). daSNV target gene analysis, combined with daSNV editing, underscored dysregulated epidermal differentiation as a shared pathomechanism. CRISPR knockout screens of 1772 human TFs revealed 123 TFs essential for epidermal homeostasis, highlighting ZNF217 and CXXC1. Population sampling CUT&RUN of 27 homeostatic TFs identified allele-specific DNA binding (ASB) differences at daSNVs enriched near epidermal homeostasis and monogenic skin disease genes, with notable representation of SP/KLF and AP-1/2 TFs. High TF-occupancy promoters were “buffered” against ASB. This resource implicates dysregulated binding of specific homeostatic TF families in risk for diverse polygenic skin diseases.

Suggested Citation

  • Douglas F. Porter & Robin M. Meyers & Weili Miao & David L. Reynolds & Audrey W. Hong & Xue Yang & Suhas Srinivasan & Smarajit Mondal & Zurab Siprashvili & Tania Fabo & Ronghao Zhou & Tri Nguyen & Luc, 2025. "Disease-linked regulatory DNA variants and homeostatic transcription factors in epidermis," Nature Communications, Nature, vol. 16(1), pages 1-28, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63070-5
    DOI: 10.1038/s41467-025-63070-5
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