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

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.

SUBMITTER: Stevens ML

PROVIDER: S-EPMC7427989 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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

Stevens Mariana L ML Zhang Zhonghua Z Johansson Elisabet E Ray Samriddha S Jagpal Amrita A Ruff Brandy P BP Kothari Arjun A He Hua H Martin Lisa J LJ Ji Hong H Wikenheiser-Brokamp Kathryn K Weirauch Matthew T MT Supp Dorothy M DM Biagini Myers Jocelyn M JM Khurana Hershey Gurjit K GK

Nature communications 20200814 1

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. Kif3a<sup>K14∆/∆</sup> mice have increased ...[more]

PMID: 32796837

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Project description:Atopic dermatitis (AD) is a widely spread cutaneous chronic disease characterised by sensitive reactions (eg. eczema) to normally innocuous elements. Although relatively little is understood about its underlying mechanisms due to its complexity, skin barrier dysfunction has been recognised as a key factor in the development of AD. Skin barrier homeostasis requires tight control of the activity of proteases, called kallikreins (KLKs), whose activity is regulated by a complex network of protein interactions that remains poorly understood despite its pathological importance. Characteristic symptoms of AD include the outbreak of inflammation triggered by external (eg. mechanical and chemical) stimulus and the persistence and aggravation of inflammation even if the initial stimulus disappears. These characteristic symptoms, together with some experimental data, suggest the presence of positive feedback regulation for KLK activity by inflammatory signals. We developed simple mathematical models for the KLK activation system to study the effects of feedback loops and carried out bifurcation analysis to investigate the model behaviours corresponding to inflammation caused by external stimulus. The model analysis confirmed that the hypothesised core model mechanisms capture the essence of inflammation outbreak by a defective skin barrier. Our models predicted the outbreaks of inflammation at weaker stimulus and its longer persistence in AD patients compared to healthy control. We also proposed a novel quantitative indicator for inflammation level by applying principal component analysis to microarray data. The model analysis reproduced qualitative AD characteristics revealed by this indicator. Our results strongly implicate the presence and importance of feedback mechanisms in KLK activity regulation. We further proposed future experiments that may provide informative data to enhance the system-level understanding on the regulatory mechanisms of skin barrier in AD and healthy individuals.

Dataset Information

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

Publications

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

Similar Datasets

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