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<p>Identifying noncoding single nucleotide variants (<Emphasis Type="Underline">SNVs</Emphasis>) in regulatory DNA linked to polygenic disease risk, the transcription factors (<Emphasis Type="Underline">TFs</Emphasis>) 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 (<Emphasis Type="Underline">daSNVs</Emphasis>). 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&amp;RUN of 27 homeostatic TFs identified allele-specific DNA binding (<Emphasis Type="Underline">ASB</Emphasis>) 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月25日

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  • 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,
  • Luca Ducoli,
  • Jordan M. Meyers,
  • Duy T. Nguyen,
  • Lisa A. Ko,
  • Laura N. Kellman,
  • Ibtihal Elfaki,
  • Margaret Guo,
  • Mårten CG Winge,
  • Leandra V. Jackrazi,
  • Vanessa Lopez-Pajares,
  • Betty B. Liu,
  • Yuanhao Qu,
  • Imani E. Porter,
  • Samuel H. Kim,
  • Gyuhyeon Kim,
  • Shiying Tao,
  • Jesse M. Engreitz,
  • Paul A. Khavari

摘要

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.