Hyperactivation of JAK1 tyrosine kinase induces stepwise, progressive pruritic dermatitis

Yasuda, Tomohiko; Fukada, Toshiyuki; Nishida, Keigo; Nakayama, Manabu; Matsushima, Masashi; Miura, Ikuo; Dainichi, Teruki; Fukuda, Shinji; Kabashima, Kenji; Nakaoka, Shinji; Bin, Bum-Ho; Kubo, Masato; Ohno, Hiroshi; Hasegawa, Takanori; Ohara, Osamu; Koseki, Haruhiko; Wakana, Shigeharu; Yoshida, Hisahiro

doi:10.1172/jci82887

Cited by 48 publications

(46 citation statements)

References 49 publications

(53 reference statements)

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“…The mesenchymal marker VIMENTIN was upregulated in PDGFC-overexpressing HHIRSCs, a finding that supports the result from the cell proliferation assay showing increasing proliferation rates ( Figures 7B, C). As a factor in EGFR tyrosine kinase inhibitor resistance signaling, JAK1 is a molecule known to perturb skin hemostasis-related pathways and induce epidermal inflammation and downstream genes associated with clinical skin diseases (Jin et al, 2014;Jabbari et al, 2015;Yasuda et al, 2016). GJA1 encodes the gap junction protein connexin 43 (Cx43) in nearly every tissue in the body, and high expression leads to increased connexin density, which has been observed in the proximal bulb of the IRS (Flores et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Integrated Analysis of Methylome and Transcriptome Changes Reveals the Underlying Regulatory Signatures Driving Curly Wool Transformation in Chinese Zhongwei Goats

et al. 2020

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The Zhongwei goat is kept primarily for its beautiful white, curly pelt that appears when the kid is approximately 1 month old; however, this representative phenotype often changes to a less curly phenotype during postnatal development in a process that may be mediated by multiple molecular signals. DNA methylation plays important roles in mammalian cellular processes and is essential for the initiation of hair follicle (HF) development. Here, we sought to investigate the effects of genome-wide DNA methylation by combining expression profiles of the underlying curly fleece dynamics. Genome-wide DNA methylation maps and transcriptomes of skin tissues collected from 45-to 108-day-old goats were used for whole-genome bisulfite sequencing (WGBS) and RNA sequencing, respectively. Between the two developmental stages, 1,250 of 3,379 differentially methylated regions (DMRs) were annotated in differentially methylated genes (DMGs), and these regions were mainly related to intercellular communication and the cytoskeleton. Integrated analysis of the methylome and transcriptome data led to the identification of 14 overlapping genes that encode crucial factors for wool fiber development through epigenetic mechanisms. Furthermore, a functional study using human hair inner root sheath cells (HHIRSCs) revealed that, one of the overlapping genes, platelet-derived growth factor C (PDGFC) had a significant effect on the messenger RNA expression of several key HF-related genes that promote cell migration and proliferation. Our study presents an unprecedented analysis that was used to explore the enigma of fleece morphological changes by combining methylome maps and transcriptional expression, and these data revealed stage-specific epigenetic changes that potentially affect fiber development. Furthermore, our functional study highlights a possible role for the overlapping gene PDGFC in HF cell growth, which may be a predictable biomarker for fur goat selection.

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Section: Discussionmentioning

confidence: 99%

Integrated Analysis of Methylome and Transcriptome Changes Reveals the Underlying Regulatory Signatures Driving Curly Wool Transformation in Chinese Zhongwei Goats

et al. 2020

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“…Moreover, 2 recently developed mouse models with a Jak1 GoF mutation share a number of similarities with the human phenotype, including skin inflammation, activation of the IL-6-JAK-STAT pathway, liver and spleen abnormalities, and autoimmune disease. 3,8,9 Our observation that JAK1/2 inhibition with ruxolitinib resolved the severe dermatitis associated with the human JAK1 GoF mutation, combined with the mechanistic insights from mouse models, 8 provides further justification for targeting JAK1 in the treatment of atopic dermatitis.…”

Section: Jak1 Gain-of-function Causes An Autosomal Dominant Immune Dymentioning

confidence: 99%

JAK1 gain-of-function causes an autosomal dominant immune dysregulatory and hypereosinophilic syndrome

Bel

Ragotte

Saferali

et al. 2017

Journal of Allergy and Clinical Immunology

104

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“…Growing evidence suggests a benefit of targeting Janus kinase in AD (Guttman-Yassky et al, 2019). In these contexts, two N-ethyl-N-nitrosoureaederived models, CARMA-1/Card11-mutant mice (Jun et al, 2003) and JAK1 spade/spade mice (Yasuda et al, 2016) might be interesting models for understanding atopic inflammation from the immune signaling perspective.…”

Section: Genetically Engineered Modelsmentioning

confidence: 99%

Research Techniques Made Simple: Mouse Models of Atopic Dermatitis

Kim

Kobayashi

2019

Journal of Investigative Dermatology

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Atopic dermatitis (AD) is a common, chronic inflammatory skin disease characterized by impaired barrier function, eczematous dermatitis, and chronic pruritus. Mouse models have been heavily used to deepen our understanding of complicated disease mechanisms in AD and to provide a preclinical platform before performing clinical interventional research on novel therapeutic agents in humans. However, what aspects of human AD these mouse AD models faithfully recapitulate is insufficiently understood. We categorized mouse AD models into three groups: (i) inbred models, (ii) genetically engineered mice in which genes of interest are overexpressed or deleted in a specific cell type, and (iii) models induced by topical application of exogenous agents. To maximize benefits from current murine AD models, understanding the strengths and limitations of each model is essential when selecting a system suitable for a specific research question. We describe known and emerging AD mouse models and discuss the usefulness and pitfalls of each system.

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Hyperactivation of JAK1 tyrosine kinase induces stepwise, progressive pruritic dermatitis

Cited by 48 publications

References 49 publications

Integrated Analysis of Methylome and Transcriptome Changes Reveals the Underlying Regulatory Signatures Driving Curly Wool Transformation in Chinese Zhongwei Goats

Integrated Analysis of Methylome and Transcriptome Changes Reveals the Underlying Regulatory Signatures Driving Curly Wool Transformation in Chinese Zhongwei Goats

JAK1 gain-of-function causes an autosomal dominant immune dysregulatory and hypereosinophilic syndrome

Research Techniques Made Simple: Mouse Models of Atopic Dermatitis

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