Disease-associated KIF3A variants alter gene methylation and expression impacting skin barrier and atopic dermatitis risk

Mariana L Stevens,Matthew T Weirauch,Hua He,Elisabet Johansson,Jocelyn M Biagini Myers,Kathryn Wikenheiser-Brokamp,Samriddha Ray,Lisa J Martin,Zhonghua Zhang,Arjun Kothari,Dorothy M Supp,Amrita Jagpal,Hong Ji,Gurjit K Khurana Hershey,Brandy P Ruff

doi:10.1038/s41467-020-17895-x

Abstract

Single nucleotide polymorphisms (SNPs) in the gene encoding kinesin family member 3A, KIF3A, have been associated with atopic dermatitis (AD), a chronic inflammatory skin disorder. We find that KIF3A SNP rs11740584 and rs2299007 risk alleles create cytosine-phosphate-guanine sites, which are highly methylated and result in lower KIF3A expression, and this methylation is associated with increased transepidermal water loss (TEWL) in risk allele carriers. Kif3aK14∆/∆ mice have increased TEWL, disrupted junctional proteins, and increased susceptibility to develop AD. Thus, KIF3A is required for skin barrier homeostasis whereby decreased KIF3A skin expression causes disrupted skin barrier function and promotes development of AD.

Highlights

Single nucleotide polymorphisms (SNPs) in the gene encoding kinesin family member 3A, kinesin family number 3A (KIF3A), have been associated with atopic dermatitis (AD), a chronic inflammatory skin disorder
KIF3A SNPs rs11740584 and rs2299007 have been associated with asthma and AD7, and both are CpG SNPs, such that the alternate or non-reference allele creates a new CpG site (Fig. 1a, b)
Our data provide a mechanistic basis for the AD disease susceptibility conferred by KIF3A SNPs rs11740584 and rs2299007 whereby the alternate alleles generate new CpG sites resulting in increased methylation and decreased expression of KIF3A

Summary

Introduction

Single nucleotide polymorphisms (SNPs) in the gene encoding kinesin family member 3A, KIF3A, have been associated with atopic dermatitis (AD), a chronic inflammatory skin disorder. We show that rs11740584 and rs2299007 AD-risk alleles create new CpG sites, which are highly methylated in individuals carrying one or two copies of the alternate allele Both SNPs are expression quantitative trait loci (eQTLs) in numerous tissues and allele-specific PCR confirms lower expression from the alternate (risk) allele compared to the reference allele. Methylation levels at these new CpG sites are associated with increased transepidermal water loss (TEWL). These data suggest that KIF3A is required for skin barrier homeostasis and decreased KIF3A expression results in skin barrier dysfunction. Our results highlight the independent role of KIF3A as a key mechanistic pathway for allergic disease pathogenesis and provide insights into the transcriptional regulation of KIF3A

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Results

Conclusion