Yi-Yin Tai, Qiujun Yu, Ying Tang, Wei Sun, Neil J. Kelly, Satoshi Okawa, Jingsi Zhao, Tae-Hwi Schwantes-An, Caroline Lacoux, Stephanie Torrino, Yassmin Al Aaraj, Wadih El Khoury, Vinny Negi, Mingjun Liu, Catherine G. Corey, Frances Belmonte, Sara O. Vargas, Brian Schwartz, Bal Bhat, B. Nelson Chau, Jason H. Karnes, Taijyu Satoh, Robert J. Barndt, Haodi Wu, Victoria N. Parikh, Jianrong Wang, Yingze Zhang, Dennis McNamara, Gang Li, Gil Speyer, Bing Wang, Sruti Shiva, Brett Kaufman, Seungchan Kim, Delphine Gomez, Bernard Mari, Michael H. Cho, Adel Boueiz, Michael W. Pauciulo, Laura Southgate, Richard C. Trembath, Olivier Sitbon, Marc Humbert, Stefan Graf, Nicholas W. Morrell, Christopher J. Rhodes, Martin R. Wilkins, Mehdi Nouraie, William C. Nichols, Ankit A. Desai, Thomas Bertero, Stephen Y. Chan

Allele-specific control of rodent and human lncRNA KMT2E-AS1 promotes hypoxic endothelial pathology in pulmonary hypertension

  • General Medicine

Hypoxic reprogramming of vasculature relies on genetic, epigenetic, and metabolic circuitry, but the control points are unknown. In pulmonary arterial hypertension (PAH), a disease driven by hypoxia inducible factor (HIF)–dependent vascular dysfunction, HIF-2α promoted expression of neighboring genes, long noncoding RNA (lncRNA) histone lysine N -methyltransferase 2E-antisense 1 ( KMT2E-AS1 ) and histone lysine N-methyltransferase 2E ( KMT2E ). KMT2E-AS1 stabilized KMT2E protein to increase epigenetic histone 3 lysine 4 trimethylation (H3K4me3), driving HIF-2α–dependent metabolic and pathogenic endothelial activity. This lncRNA axis also increased HIF-2α expression across epigenetic, transcriptional, and posttranscriptional contexts, thus promoting a positive feedback loop to further augment HIF-2α activity. We identified a genetic association between rs73184087, a single-nucleotide variant (SNV) within a KMT2E intron, and disease risk in PAH discovery and replication patient cohorts and in a global meta-analysis. This SNV displayed allele (G)–specific association with HIF-2α, engaged in long-range chromatin interactions, and induced the lncRNA-KMT2E tandem in hypoxic (G/G) cells. In vivo, KMT2E-AS1 deficiency protected against PAH in mice, as did pharmacologic inhibition of histone methylation in rats. Conversely, forced lncRNA expression promoted more severe PH. Thus, the KMT2E-AS1 /KMT2E pair orchestrates across convergent multi-ome landscapes to mediate HIF-2α pathobiology and represents a key clinical target in pulmonary hypertension.

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