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

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 and Paul A. Khavari ()
Additional contact information
Douglas F. Porter: Stanford University School of Medicine
Robin M. Meyers: 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
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
Tri Nguyen: Stanford University School of Medicine
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
Ibtihal Elfaki: Stanford University School of Medicine
Margaret Guo: Stanford University School of Medicine
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
Samuel H. Kim: Stanford University School of Medicine
Gyuhyeon Kim: Stanford University School of Medicine
Shiying Tao: Stanford University School of Medicine
Jesse M. Engreitz: Stanford University School of Medicine
Paul A. Khavari: Stanford University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-28

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-63070-5

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