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- Title
Allele-specific control of rodent and human lncRNA KMT2E-AS1 promotes hypoxic endothelial pathology in pulmonary hypertension.
- Authors
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
- Abstract
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. Editor's summary: Pulmonary arterial hypertension (PAH) is regulated by the effects of hypoxia on the endothelium, but how epigenetics and metabolism are involved has been unclear. Here, Tai et al. showed that the long noncoding RNA histone lysine N-methyltransferase 2E-antisense 1 (KMT2E-AS1) and its protein binding partner KMT2E act in a positive feedback loop with HIF-2α to exacerbate PAH through epigenetic and metabolic changes. They confirmed that a gene variant in KMT2E was associated with PAH risk in several patient cohorts. Pharmacologically inhibiting the epigenetic changes in a rat model of PAH reversed pathology, suggesting that this pathway may be a promising target for diagnosis and treatment of PAH in humans. —Brandon Berry
- Subjects
PULMONARY hypertension; RODENT control; PULMONARY arterial hypertension; GENE expression; LINCRNA; EPIGENOMICS; TYPE 2 diabetes; ENDOTHELIUM diseases; HYPOXIA-inducible factor 1
- Publication
Science Translational Medicine, 2024, Vol 16, Issue 729, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.add2029