Lamin A K97E leads to NF-κB-mediated dysfunction of inflammatory responses in dilated cardiomyopathy

IF 2.4 4区 生物学 Q4 CELL BIOLOGY Biology of the Cell Pub Date : 2024-02-25 DOI:10.1111/boc.202300094
Duhita Sengupta, Kaushik Sengupta
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Abstract

Background Information

Lamins are type V intermediate filament proteins underlying the inner nuclear membrane which provide structural rigidity to the nucleus, tether the chromosomes, maintain nuclear homeostasis, and remain dynamically associated with developmentally regulated regions of the genome. A large number of mutations particularly in the LMNA gene encoding lamin A/C results in a wide array of human diseases, collectively termed as laminopathies. Dilated Cardiomyopathy (DCM) is one such laminopathic cardiovascular disease which is associated with systolic dysfunction of left or both ventricles leading to cardiac arrhythmia which ultimately culminates into myocardial infarction.

Results

In this work, we have unraveled the epigenetic landscape to address the regulation of gene expression in mouse myoblast cell line in the context of the missense mutation LMNA 289A<G (Lys97Glu) that is found in DCM-afflicted patient with severe symptoms. Significant changes in H3-specific epigenetic modifications indicated a dysregulation in transcription machinery which was investigated by RNA sequencing analysis. The major pathways involved in IL-17 signaling, cellular response to interferon-beta and gamma, cytokine production, and related pathways are found to be downregulated. Analysis of the promoter sequences of the genes in the abovementioned pathways led us to the master regulator NF-κB and its regulatory network.

Conclusions

We report here for the first time that there is a significant downregulation of the NF-κB pathway, which has been implicated in cardio-protection elsewhere.

Significance

This provides a new pathophysiological explanation that correlates an LMNA mutation and dilated cardiomyopathy.

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Lamin A K97E导致扩张型心肌病中NF-κB介导的炎症反应功能障碍。
背景信息片层蛋白是核内膜底层的 V 型中间丝蛋白,它为细胞核提供结构刚度,拴住染色体,维持核平衡,并与基因组中受发育调控的区域保持动态关联。大量基因突变,尤其是编码片层蛋白 A/C的 LMNA 基因突变,导致了一系列人类疾病,统称为片层蛋白病。扩张型心肌病(DCM)就是这样一种板层病心血管疾病,它与左心室或双心室收缩功能障碍有关,导致心律失常,最终导致心肌梗死:在这项工作中,我们揭开了表观遗传学的面纱,研究了小鼠成肌细胞系在LMNA 289AC错义突变背景下的基因表达调控:我们在此首次报告了NF-κB通路的显著下调,该通路在其他地方被认为与心脏保护有关:意义:这提供了一种新的病理生理学解释,将 LMNA 突变与扩张型心肌病联系起来。
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来源期刊
Biology of the Cell
Biology of the Cell 生物-细胞生物学
CiteScore
5.30
自引率
0.00%
发文量
53
审稿时长
>12 weeks
期刊介绍: The journal publishes original research articles and reviews on all aspects of cellular, molecular and structural biology, developmental biology, cell physiology and evolution. It will publish articles or reviews contributing to the understanding of the elementary biochemical and biophysical principles of live matter organization from the molecular, cellular and tissues scales and organisms. This includes contributions directed towards understanding biochemical and biophysical mechanisms, structure-function relationships with respect to basic cell and tissue functions, development, development/evolution relationship, morphogenesis, stem cell biology, cell biology of disease, plant cell biology, as well as contributions directed toward understanding integrated processes at the organelles, cell and tissue levels. Contributions using approaches such as high resolution imaging, live imaging, quantitative cell biology and integrated biology; as well as those using innovative genetic and epigenetic technologies, ex-vivo tissue engineering, cellular, tissue and integrated functional analysis, and quantitative biology and modeling to demonstrate original biological principles are encouraged.
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