Inhibition of H3K27me3 demethylases attenuates asthma by reversing the shift in airway smooth muscle phenotype

Yu, Qijun; Yu, Xiaowei; Zhao, Wenxue; Zhu, Manni; Wang, Zhengxia; Zhang, Jiaxiang; Huang, Mao; Zeng, Xianlu

doi:10.1111/cea.13244

Cited by 22 publications

(15 citation statements)

References 56 publications

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“…However, the damaged lung function was improved after the instillation of PRMT6. Yu et al 20 used a demethylase inhibitor, which could modulate cell function by targeting H3K27 in airway smooth muscle cells, to treat asthma mice. They found that both lungresistance and Cdyn were improved, and this inhibitor could attenuate airway remodeling via Akt/MAPKs signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

PRMT6 mediates inflammation via activation of the NF-κB/ p65 pathway on a cigarette smoke extract-induced murine emphysema model

Luo

et al. 2020

Tob. Induc. Dis.

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INTRODUCTION Smoke-driven lung inflammation is considered to be the major pathophysiology mechanism of Chronic Obstructive Pulmonary Disease (COPD)/ emphysema. Protein arginine methyltransferase 6 (PRMT6) is a key epigenetic enzyme, which is related to protecting the tri-methylation of H3K4 (H3K4me3). We hypothesized that PTMT6 protects lung inflammation through the nuclear factor kappa B (NF-κB) pathway. METHODS Mice were injected with cigarette smoke extract (CSE) or PBS to establish a mice model, intratracheally instilled with overexpressed PRMT6 or negative control vector. Morphometry of lung slides and lung function were measured. We determined the protein expression of PRMT6 and its related histone targets, the activation of NF-κB pathway, the level of tumor necrosis factor α (TNFα) and interleukin-1β (IL-1β). RESULTS After PRMT6 overexpression, the morphometry indexes and lung function were improved. Also, the expression of H3K4me3 was decreased. Overexpressed PRMT6 could suppress CSE-induced NF-κB activation and pro-inflammation genes expression. CONCLUSIONS The overexpressed PRMT6 could serve as an inflammation inhibitor, potentially through blocking the NF-κB/p65 pathway in the murine emphysema model.

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Section: Discussionmentioning

confidence: 99%

PRMT6 mediates inflammation via activation of the NF-κB/ p65 pathway on a cigarette smoke extract-induced murine emphysema model

Luo

et al. 2020

Tob. Induc. Dis.

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“…This small molecule inhibitor was further modified by adding cell penetrating ethyl esters to produce GSK-J4, which inhibited LPS-induced cytokine expression in macrophages of healthy volunteers (Kruidenier et al 2012). GSK-J4 was further shown to decrease airway smooth muscle cells (ASMCs) proliferation and migration in the contractive model of human ASMCs (Yu et al 2018). GSK-J4 was also found efficient in blocking the growth of neuroblastoma cell and GSK-J4 and RA combination inhibited patient-derived xenograft models of high-risk neuroblastoma growth in vivo more (Lochmann et al 2018).…”

Section: Discussionmentioning

confidence: 99%

JMJD3 in the regulation of human diseases

et al. 2019

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In recent years, many studies have shown that histone methylation plays an important role in maintaining the active and silent state of gene expression in human diseases. The Jumonji domain-containing protein D3 (JMJD3), specifically demethylate di- and trimethyl-lysine 27 on histone H3 (H3K27me2/3), has been widely studied in immune diseases, infectious diseases, cancer, developmental diseases, and aging related diseases. We will focus on the recent advances of JMJD3 function in human diseases, and looks ahead to the future of JMJD3 gene research in this review.

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“…Ezh2 further prevents the development of pathological NKT cells preventing a spontaneous asthma-like phenotype in experimental models [112]. First results show also the possibility of improving allergic inflammation and airway hyperresponsiveness in experimental asthma models by administrating a H3K27Me3 specific histone demethylase inhibitor (GSK-J4 [113]).…”

Section: A Potential Next Step: Targeting Epigenetic Enzymes In Allermentioning

confidence: 94%

Recent findings in the genetics and epigenetics of asthma and allergy

Kabesch¹,

Tost

2020

Semin Immunopathol

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In asthma and allergy genetics, a trend towards a few main topics developed over the last 2 years. First, a number of studies have been published recently which focus on overlapping and/or very specific phenotypes: within the allergy spectrum but also reaching beyond, looking for common genetic traits shared between different diseases or disease entities. Secondly, an urgently needed focus has been put on asthma and allergy genetics in populations genetically different from European ancestry. This acknowledges that the majority of new asthma patients today are not white and asthma is a truly worldwide disease. In epigenetics, recent years have seen several large-scale epigenome-wide association studies (EWAS) being published and a further focus was on the interaction between the environment and epigenetic signatures. And finally, the major trends in current asthma and allergy genetics and epigenetics comes from the field of pharmacogenetics, where it is necessary to understand the susceptibility for and mechanisms of current asthma and allergy therapies while at the same time, we need to have scientific answers to the recent availability of novel drugs that hold the promise for a more individualized therapy.

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Inhibition of H3K27me3 demethylases attenuates asthma by reversing the shift in airway smooth muscle phenotype

Abstract: Inhibition of H3K27me3 demethylation alleviated the development of asthmatic airway disease in vivo and modulated ASMCs phenotype in vitro. Collectively, our findings highlight a role of H3K27me3 demethylation in experimental asthma and ASMCs phenotype switch.

Cited by 22 publications

References 56 publications

PRMT6 mediates inflammation via activation of the NF-κB/ p65 pathway on a cigarette smoke extract-induced murine emphysema model

PRMT6 mediates inflammation via activation of the NF-κB/ p65 pathway on a cigarette smoke extract-induced murine emphysema model

JMJD3 in the regulation of human diseases

Recent findings in the genetics and epigenetics of asthma and allergy

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