Disease-linked regulatory DNA variants and homeostatic transcription factors in epidermis
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.
Article Details
Authors (30)
Douglas F. Porter
Robin M. Meyers
Weili Miao
David L. Reynolds
Program in Epithelial Biology, Stanford University School of Medicine
Audrey W. Hong
Xue Yang
Suhas Srinivasan
Smarajit Mondal
Program in Epithelial Biology, Stanford University School of Medicine
Zurab Siprashvili
Program in Epithelial Biology, Stanford University School of Medicine
Tania Fabo
Ronghao Zhou
Tri Nguyen
Luca Ducoli
Jordan M. Meyers
Duy T. Nguyen
Lisa A. Ko
Program in Epithelial Biology, Stanford University, Stanford, CA, USA.
Laura N. Kellman
Ibtihal Elfaki
Margaret Guo
Mårten CG Winge
Leandra V. Jackrazi
Vanessa Lopez-Pajares
Betty B. Liu
Yuanhao Qu
Phylo, Inc., South San Francisco, CA, USA.
Imani E. Porter
Samuel H. Kim
Gyuhyeon Kim
Shiying Tao
Program in Epithelial Biology, Stanford University School of Medicine
Jesse M. Engreitz
Paul A. Khavari