Super-Enhancer–Driven HCG20 Promotes Pulmonary Hypertension Through U2AF2 Splicing

• DOI: 10.1161/circresaha.125.326133
• Publication Date: 2025-05-28T09:00:15Z
• Authors: Jian Mei; Wei Huang; Zitong Meng; Shiqing Wen; Langlin Ou; June Bai; Xiaoying Wang; Hao Yuan; Yanyu Li; Lixin Zhang; Yuwei You; Yingli Chen; Xiaodong Zheng; Fei Li; Song Wang; Xiangrui Zhu; Zhaosi Wang; Daling Zhu; Xiaowei Nie; Cui Ma

BACKGROUND: Pulmonary artery endothelial cell (PAEC) dysfunction is a pathological hallmark of pulmonary hypertension (PH). Yet, the roles long noncoding RNAs (lncRNAs) driven by super-enhancers (SEs) in PAECs are not well understood. In this study, we focused on PAEC-specific SE-associated lncRNA HCG20 (HLA complex group 20) and to elucidate its role underlying mechanisms progression PH. METHODS: ChIP-qPCR, chromosome conformation capture followed PCR, CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered repeat-associated 9), dual-luciferase reporter assays were used identify dysregulated lncRNAs investigate HCG20. The processes was validated rodent models PH induced SU5416/hypoxia, monocrotaline, or hypoxia alone, through adeno-associated virus–mediated endothelial-specific overexpression knockdown RNA pull-down, mass spectrometry, immunoprecipitation, sequencing HCG20-mediated PAEC dysfunction. RESULTS: We identified from histone H3 lysine-27 acetylation (H3K27ac) lysine-4 monomethylation (H3K4me1) ChIP-seq data derived patients with A significant upregulation found hypoxia-induced human PAECs, lung tissues, plasma Antisense oligonucleotide CRISPR/Cas9, which, respectively, target SE, alleviate pyroptosis subsequent endothelial-to-mesenchymal transition. Human smooth muscle cells internalize PAEC–derived exosomes containing HCG20, inducing their excessive proliferation. Targeted delivery into vascular endothelium vasculature remodeling increased systolic blood pressure rodents. Mechanistically, directly bound stabilized U2AF2 (U2 small nuclear auxiliary factor 2) protein, thereby facilitating impact alternative splicing EIF2AK2 (eukaryotic translation initiation 2 alpha kinase 2). Furthermore, novel mouse ortholog gene, 4833427F10Rik (named Hcg20), for first time. Our study demonstrated that specific interference Hcg20 intima has been shown ameliorate CONCLUSIONS: Collectively, our suggest contributes U2AF2-mediated EIF2AK2. work underscores potential using as biomarker promising treatment