Super enhancer-driven LINC01013 mediates hypoxia-induced mitochondrial dysfunction by HSPA9 to determine pulmonary arterial smooth muscle cell fate.

Super-enhancers (SEs) typically govern the expression of critical genes in the maintenance of cell identity. Recent advances suggest mitochondrial dysfunction contributes to pulmonary artery smooth muscle cell (PASMC) proliferation and inflammation in pulmonary hypertension (PH). However, the landscape of SEs in hypoxic PASMCs as well as hypoxia-induced target genes associated with SEs controlling the mitochondrial dysfunction remain to be fully characterized. In this study, we depicted the landscape of SE in hypoxic PASMCs by ChIP-seq, Hi-ChIP, and ChIP-qPCR assays and reveal a regulatory SE driven LncRNA, LINC01013. The effect of LINC01013 on proliferation and inflammation of PASMCs was evaluated through EdU incorporation, Western blotting and immunofluorescence. The molecular mechanism of LINC01013 was investigated by the study of RNA pull down and mass spectrometry. We profiled chromosome interactions in epigenetic regulation and identified SE-associated LINC01013 as a key mitochondrial dysfunction mediator in hypoxic PASMCs. The transcription factor CCAAT enhancer binding protein beta (CEBPB) was found to enrichment in LINC01013 SE and promoter, promoting LINC01013 transcription and overexpression in PASMCs under hypoxic conditions. Inhibition of LINC01013 reversed hypoxia-induced glycolysis and oxidative stress injury of PASMCs. Further investigation unveiled that LINC01013, which is partially located in mitochondria and interacted with heat shock protein family A member 9 (HSPA9) to mediate oligomerization of voltage dependent anion channel 1 (VDAC1), thereby leading to increased mitochondrial permeability and dysfunction. These findings demonstrate that SE-associated LINC01013 regulates the proliferation and inflammation of hypoxic PASMCs by orchestrating mitochondrial function, might be a potential therapeutic target for PH.