# Regulatory Variants in HUMAN SKIN DISEASES

> **NIH NIH R01** · STANFORD UNIVERSITY · 2021 · $470,721

## Abstract

VARIANTS IN HUMAN SKIN DISEASE
PROJECT SUMMARY
 Transcription factors (TFs) bind regulatory DNA to control differentiation genes in normal and
diseased tissue, including cutaneous epidermis. We mapped regulatory DNA active in human
epidermis and found it enriched for single nucleotide polymorphisms (eSNPs, for “expression SNPs”)
linked by genome-wide association studies (GWAS) to inflammatory skin diseases in which altered
epidermal differentiation contributes to pathogenesis, including atopic dermatitis (AD) and psoriasis
vulgaris (PV). AD and PV-linked eSNPs alter DNA motifs and transcription-directing activity in human
keratinocytes, suggesting they serve as binding quantitative trait loci (bQTLs) for TFs whose modified
activity at these sites pathogenically dysregulates target genes (eGenes). Such eSNP regulatory
variants, the TFs whose binding they alter, and the eGenes whose expression they dysregulate, form a
regulatory risk framework for polygenic disease. This proposal will elucidate features of such regulatory
risk frameworks in the context of human tissue, using AD and PV as polygenic disease prototypes.
 First, we will define phenotypic impacts of disease-linked eSNPs in human skin tissue, focusing on
the epidermis-intrinsic component of AD and PV. We will assess disease eSNP impacts on the gene
expression, architecture and function of intact human epidermal tissue. To do this, we will generate
otherwise identical, isogenic human skin xenografts that differ only by the single regulatory DNA
nucleotides studied using a hybrid gene editing approach. eSNPs will be studied singly and in
combination. Aim I will define the impacts of AD and PV-linked regulatory variants in human tissue.
 Second, we will identify the TFs whose DNA binding and function is changed at specific eSNPs to
extend understanding of disease-linked regulatory DNA variants to the level of biochemical mechanism.
To do this, we will use new proteomic and genetic methods. The first method, DNA Protein
Identification Detection (DAPID) uses DNA-tethered proximity proteomics to detect and quantify TF
binding to any DNA sequence of interest in living cells. The second, Perturb-MPRA, couples CRISPR
screening to the massively parallel reporter assay (MPRA) to identify the TFs essential for the
transcriptional activity directed by any DNA sequence. Aim II will identify the TFs whose DNA binding
and activity is affected by disease-linked eSNPs in AD and PV.
 This project will use new methods and a human tissue context to define the eSNP, TF, and eGene
regulatory risk frameworks in common human polygenic skin diseases.

## Key facts

- **NIH application ID:** 10149248
- **Project number:** 5R01AR076965-02
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** PAUL KHAVARI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $470,721
- **Award type:** 5
- **Project period:** 2020-05-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10149248

## Citation

> US National Institutes of Health, RePORTER application 10149248, Regulatory Variants in HUMAN SKIN DISEASES (5R01AR076965-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10149248. Licensed CC0.

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