Disease-linked regulatory DNA variants and homeostatic transcription factors in epidermis
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.
Authors
- Shiying Tao
- Paul A. Khavari (ORCID: https://orcid.org/0000-0003-0098-4989)
- Smarajit Mondal (ORCID: https://orcid.org/0000-0002-2883-2728)
- Imani E. Porter (ORCID: https://orcid.org/0000-0003-0043-2658)
- Tania Fabo (ORCID: https://orcid.org/0000-0002-8987-0672)
- Nguyen Tri Quang Hung (ORCID: https://orcid.org/0000-0001-5165-757X)
- Jordan M. Meyers (ORCID: https://orcid.org/0000-0003-0206-0886)
- Margaret Guo (ORCID: https://orcid.org/0000-0001-7713-3846)
- Suhas Srinivasan (ORCID: https://orcid.org/0000-0001-8309-9648)
- Gyuhyeon Kim
- Ronghao Zhou (ORCID: https://orcid.org/0000-0002-3917-0694)
- Lisa A. Ko (ORCID: https://orcid.org/0000-0002-3732-0580)
- David L. Reynolds (ORCID: https://orcid.org/0000-0001-5929-3475)
- Xue Yang (ORCID: https://orcid.org/0000-0002-1288-5569)
- Weili Miao (ORCID: https://orcid.org/0000-0002-7487-8962)
- Duy T. Nguyen (ORCID: https://orcid.org/0000-0001-6570-6010)
- Luca Ducoli (ORCID: https://orcid.org/0000-0003-1731-9029)
- M.C.G. Winge (ORCID: https://orcid.org/0000-0001-6119-6009)
- Vanessa Lopez-Pajares (ORCID: https://orcid.org/0000-0001-8538-344X)
- Laura N. Kellman (ORCID: https://orcid.org/0000-0002-1073-8936)
- Robin M. Meyers (ORCID: https://orcid.org/0000-0002-1802-7231)
- Ibtihal Elfaki (ORCID: https://orcid.org/0000-0002-9951-9974)
- Zurab Siprashvili (ORCID: https://orcid.org/0000-0002-2814-4220)
- Douglas F. Porter (ORCID: https://orcid.org/0000-0001-9491-8258)
- Yuanhao Qu (ORCID: https://orcid.org/0000-0002-7574-259X)
- Samuel H. Kim (ORCID: https://orcid.org/0000-0001-8353-6190)
- Yuan Liu (ORCID: https://orcid.org/0000-0003-1655-7164)
- J Engreitz (ORCID: https://orcid.org/0000-0002-5754-1719)
- Audrey W. Hong (ORCID: https://orcid.org/0000-0002-6230-9260)
- Leandra V. Jackrazi (ORCID: https://orcid.org/0000-0003-2077-329X)
Institutions
- Broad Institute (US)
- Lucile Packard Children's Hospital (US)
- Hampton University (US)
- VA Palo Alto Health Care System (US)
- Cardiovascular Institute of the South (US)
- Foundation Center (US)
- Novo Nordisk (United States) (US)
- Stanford Medicine (US)
- Stanford University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-09-25
- DOI
- https://doi.org/10.1038/s41467-025-63070-5
- Citations
- 2
- Primary Topic
- CRISPR and Genetic Engineering
- Type
- article
- Field-Weighted Citation Impact
- 1.61