Dataset Information

Multi-omics Analysis of Skeletal Muscle Identifies Dysregulation of Hypoxia-Induced Genes in Peripheral Artery Disease [RNA-seq]

ABSTRACT: 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. In this study, we used reduced representation bisulphite sequencing (RRBS) to investigate how PAD affects the DNA methylome in skeletal muscle of PAD patients with intermittent claudication (IC) or critical limb ischemia (CLI) compared to non-PAD controls. We also used small and bulk RNA-sequencing (RNA-seq), which allowed for data integration. This multi-omics approach identified metabolic and hypoxia-related genes in PAD skeletal muscle that are regulated at the level of methylation and by various microRNAs. Specifically, binding and expression target analysis (BETA) revealed that epigenetic modifications to the DNA methylome contribute to modulation of the mRNA expression of family with sequence similarity 20, member C (FAM20C) and endothelial PAS domain-containing protein 1 (EPAS1), also known as hypoxia-inducible factor-2alpha (HIF-2α). Finally, we explored the effect of revascularization on the skeletal muscle DNA methylome and transcriptome, which identified the activator protein-1 (AP-1) early response transcription factor Fos proto-oncogene (FOS) as the primary gene influenced by revascularization. These results identify novel hypoxia-related genes regulated by DNA methylation in PAD skeletal muscle, which may provide potential new therapeutic targets.

ORGANISM(S): Homo sapiens

PROVIDER: GSE289574 | GEO | 2025/10/01

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Background Peripheral artery disease (PAD) is caused by atherosclerosis and chronic narrowing of lower limb arteries leading to decreased muscle perfusion and oxygenation. Current guidelines for treating PAD include endovascular strategies or bypass surgery but long-term outcomes have been suboptimal. This is likely due to our limited understanding of the contribution of the microvasculature as well as other cell types, in particular macrophages, to PAD skeletal muscle pathophysiology. We used single cell sequencing to investigate cellular and transcriptional heterogeneity of the skeletal muscle microenvironment in PAD. Methods Samples from the medial head of the gastrocnemius muscle of individuals undergoing either lower limb aneurysm surgery (controls) or PAD bypass surgery (PAD) were collected. Samples were either frozen for histological evaluation (control: n=4; PAD: n=6) or were immediately processed for single cell RNA sequencing of mononuclear cells (control: n=4; PAD: n= 4). Bioinformatic tools were used to annotate cell types and their subpopulations, to study transcriptional changes and to analyze cellular interactions. Results We generated a dataset comprised of 106,566 high-quality, deep-sequenced cells that compose the muscle microenvironment. Focusing on endothelial cells (ECs) and macrophages, we confirmed the presence of ATF3/4+ ECs with angiogenic and immune regulatory capacities in human muscle and found that their transcriptional profile profoundly alters during PAD. Also, capillary ECs display features of endothelial to mesenchymal transition. Furthermore, we identified LYVE1hiMHCIIlow resident macrophages as the dominant macrophage population in human muscle, even under a chronic inflammatory condition such as PAD. During PAD, LYVE1hiMHCIIlow macrophages get activated and acquire a more pro-inflammatory profile. Finally, we map strong intercellular communication in the muscle microenvironment, which is significantly altered in PAD. Conclusions The dataset we present here provides a highly valuable resource for gaining deeper insights into the critical roles that cells in the muscle microenvironment may play in PAD skeletal muscle pathology. We propose that targeting the crosstalk between ECs and macrophages could provide novel insights for developing effective treatments against this disease.

Dataset Information

Multi-omics Analysis of Skeletal Muscle Identifies Dysregulation of Hypoxia-Induced Genes in Peripheral Artery Disease [RNA-seq]

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets