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Single-cell transcriptomes and chromatin accessibility of endothelial cells unravel transcription factors associated with dysregulated angiogenesis in systemic sclerosis

染色质 转录组 血管生成 细胞生物学 生物 转录因子 染色质免疫沉淀 癌症研究 免疫学 医学 基因 基因表达 遗传学 发起人
作者
Meng Huang,Tracy Tabib,Dinesh Khanna,Shervin Assassi,Robyn T. Domsic,Robert Lafyatis
出处
期刊:Annals of the Rheumatic Diseases [BMJ]
卷期号:: ard-225415 被引量:2
标识
DOI:10.1136/ard-2023-225415
摘要

Objectives Vasculopathy emerges early in systemic sclerosis (SSc) and links to endothelial cell (EC) injury and angiogenesis. Understanding EC transcriptomes and epigenomes is crucial for unravelling the mechanisms involved. Methods Transcriptomes and chromatin accessibility were assessed by single-cell RNA sequencing and single-nucleus transposase-accessible chromatin sequencing. Immunofluorescent staining of skin and proteomics assay were employed to confirm the altered SSc EC phenotypes. Gain-of-function assay was used to evaluate the effects of ETS transcription factors on human dermal ECs (hDECs). Results Both control and SSc ECs shared transcriptomic signatures of vascular linages (arterial, capillary and venous ECs) and lymphatic ECs. Arterial ECs in SSc showed reduced number and increased expression of genes associated with apoptosis. Two distinct EC subpopulations, tip and proliferating ECs, were markedly upregulated in SSc, indicating enhanced proangiogenic and proliferative activities. Molecular features of aberrant SSc-ECs were associated with disease pathogenesis and clinical traits of SSc, such as skin fibrosis and digital ulcers. Ligand-receptor analysis demonstrated altered intercellular networks of SSc EC subpopulations with perivascular and immune cells. Furthermore, the integration of open chromatin profiles with transcriptomic analysis suggested an increased accessibility of regulatory elements for ETS family transcription factors in SSc ECs. Overexpression of ETS genes in hDECs suggested ELK4, ERF and ETS1 may orchestrate arterial apoptosis and dysregulated angiogenesis in SSc. Conclusions This study unveils transcriptional and chromatin alterations in driving endovascular dysregulation in SSc, proposing ELK4, ERF and ETS1 as novel targets in ECs for addressing vascular complications in the condition.
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