骨骼肌多组学分析发现外周动脉疾病中缺氧诱导的基因失调。

IF 5.3 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS
Journal of the American Heart Association Pub Date : 2025-10-07 Epub Date: 2025-09-30 DOI:10.1161/JAHA.125.042350
Ahmed Ismaeel, Emma Fletcher, Evlampia Papoutsi, Nicholas T Thomas, William T Bohannon, Iraklis I Pipinos, Yuan Wen, Dimitrios Miserlis, Panagiotis Koutakis
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引用次数: 0

摘要

背景:表观遗传修饰如DNA甲基化在缺氧细胞程序中起关键作用。然而,之前没有研究调查外周动脉疾病(PAD)中基因表达的表观遗传调控,PAD是一种以间歇性缺血为特征的疾病。我们的研究旨在研究与非PAD对照组相比,PAD如何影响伴有间歇性跛行或严重肢体缺血的PAD患者骨骼肌DNA甲基组。方法:这是一项横断面研究,在非pad对照组、间歇性跛行和严重肢体缺血的骨骼肌中,使用亚硫酸氢盐低代表性测序和小体积RNA测序来评估DNA甲基组和转录组的差异。我们还通过比较间歇性跛行患者在基线和血运重建术后6个月的DNA甲基化和基因表达的变化。结果:多组学方法确定了PAD骨骼肌中与缺氧相关的基因,这些基因可能在甲基化水平上受到调节。具体来说,结合和表达靶标分析显示,DNA甲基组的表观遗传修饰可能有助于调节序列相似家族20、成员C和内皮PAS结构域蛋白1(也称为缺氧诱导因子-2α)的mRNA表达。此外,AP-1(激活蛋白-1)早期反应转录因子FOS和FOSB可能是受血运重建手术影响的主要基因。结论:我们的研究结果确定了PAD骨骼肌中可能受DNA甲基化调控的新型缺氧相关基因。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Multiomics Analysis of Skeletal Muscle Identifies Dysregulation of Hypoxia-Induced Genes in Peripheral Artery Disease.

Background: Epigenetic modifications such as DNA methylation play a critical role in hypoxic cell programs. However, no previous studies have investigated the epigenetic regulation of gene expression in peripheral artery disease (PAD), a condition characterized by intermittent ischemia. Our study aims to examine how PAD affects the DNA methylome in skeletal muscle of patients with PAD with intermittent claudication or critical limb ischemia compared with non-PAD controls.

Methods: This was a cross-sectional study evaluating differences in the DNA methylome and transcriptome using reduced representation bisulfite sequencing, and small and bulk RNA sequencing, in skeletal muscle from non-PAD controls, intermittent claudication, and critical limb ischemia. We also assessed changes in DNA methylation and gene expression by comparing patients with intermittent claudication at baseline and 6 months following revascularization operation.

Results: The multiomics approach identified hypoxia-related genes in PAD skeletal muscle that are potentially regulated at the level of methylation. Specifically, binding and expression target analysis revealed that epigenetic modifications to the DNA methylome may contribute to modulation of the mRNA expression of family with sequence similarity 20, member C and endothelial PAS domain-containing protein 1, also known as hypoxia-inducible factor-2α. Furthermore, the AP-1 (activator protein-1) early response transcription factors FOS and FOSB emerged as the primary genes that may be influenced by revascularization operations.

Conclusions: Our findings identify novel hypoxia-related genes potentially regulated by DNA methylation in PAD skeletal muscle.

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来源期刊
Journal of the American Heart Association
Journal of the American Heart Association CARDIAC & CARDIOVASCULAR SYSTEMS-
CiteScore
9.40
自引率
1.90%
发文量
1749
审稿时长
12 weeks
期刊介绍: As an Open Access journal, JAHA - Journal of the American Heart Association is rapidly and freely available, accelerating the translation of strong science into effective practice. JAHA is an authoritative, peer-reviewed Open Access journal focusing on cardiovascular and cerebrovascular disease. JAHA provides a global forum for basic and clinical research and timely reviews on cardiovascular disease and stroke. As an Open Access journal, its content is free on publication to read, download, and share, accelerating the translation of strong science into effective practice.
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