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

Jian Mei1, Wei Huang2, Zitong Meng1

  • 1College of Medical Laboratory Science and Technology (J.M., Z.M., S. Wen, L.O., L.Z., Y.C., X. Zheng, X. Zhu, Z.W., D.Z., C.M.), Harbin Medical University, Daqing, PR China.

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|May 28, 2025
PubMed
Summary
This summary is machine-generated.

Super-enhancer-driven lncRNA HCG20 promotes pulmonary hypertension by causing pulmonary artery endothelial cell dysfunction. Targeting HCG20 offers a potential therapeutic strategy for treating pulmonary hypertension.

Keywords:
RNA, long non-codingalternative splicinghypertension, pulmonaryhypoxiasuper enhancers

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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.