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

Area of Science:

• Molecular Biology
• Genomics
• Cardiovascular Research

Background:

• Pulmonary artery endothelial cell (PAEC) dysfunction is central to pulmonary hypertension (PH).
• The role of super-enhancer (SE)-driven long noncoding RNAs (lncRNAs) in PAECs remains unclear.
• This study investigates the SE-associated lncRNA HCG20 in PH pathogenesis.

Purpose of the Study:

• To identify and characterize the function of SE-associated lncRNAs in PAECs.
• To elucidate the mechanisms by which HCG20 contributes to PH.
• To evaluate HCG20 as a potential therapeutic target for PH.

Main Methods:

• ChIP-seq to identify SE-associated lncRNAs in PH PAECs.
• CRISPR/Cas9 and antisense oligonucleotides for HCG20 manipulation.
• Rodent models of PH for in vivo validation.
• RNA pull-down, mass spectrometry, and RNA-seq to determine molecular mechanisms.

Main Results:

• HCG20 was significantly upregulated in PH PAECs, lung tissues, and plasma.
• HCG20 inhibition alleviated hypoxia-induced PAEC pyroptosis and endothelial-to-mesenchymal transition.
• HCG20 promoted pulmonary vascular remodeling and increased pulmonary artery pressure in vivo.
• HCG20 stabilizes U2AF2, affecting EIF2AK2 alternative splicing.

Conclusions:

• SE-driven HCG20 exacerbates PAEC dysfunction and PH progression.
• HCG20 acts via the U2AF2-EIF2AK2 pathway.
• HCG20 represents a promising biomarker and therapeutic target for PH.