Allele-specific control of rodent and human lncRNA KMT2E-AS1 promotes hypoxic endothelial pathology in pulmonary hypertension.
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Tai Yi-Yin, Yu Qiujun, Tang Ying, Sun Wei, Kelly Neil J, Okawa Satoshi, Zhao Jingsi, Schwantes-An Tae-Hwi, Lacoux Caroline, Torrino Stephanie, Al Aaraj Yassmin, El Khoury Wadih, Negi Vinny, Liu Mingjun, Corey Catherine G, Belmonte Frances, Vargas Sara O, Schwartz Brian, Bhat Bal, Chau B Nelson, Karnes Jason H, Satoh Taijyu, Barndt Robert J, Wu Haodi, Parikh Victoria N, Wang Jianrong, Zhang Yingze, McNamara Dennis, Li Gang, Speyer Gil, Wang Bing, Shiva Sruti, Kaufman Brett, Kim Seungchan, Gomez Delphine, Mari Bernard, Cho Michael H, Boueiz Adel, Pauciulo Michael W, Southgate Laura, Trembath Richard C, Sitbon Olivier, Humbert Marc, Graf Stefan, Morrell Nicholas W, Rhodes Christopher J, Wilkins Martin R, Nouraie Mehdi, Nichols William C, Desai Ankit A, Bertero Thomas, Chan Stephen Y
Аннотация
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.