Browsing by Author "Southgate, Laura"

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    Allele-specific control of rodent and human lncRNA KMT2E-AS1 promotes hypoxic endothelial pathology in pulmonary hypertension
    (American Association for the Advancement of Science, 2024) 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.; Medicine, School of 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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    Defining the clinical validity of genes reported to cause pulmonary arterial hypertension
    (Elsevier, 2023) Welch, Carrie L.; Aldred, Micheala A.; Balachandar, Srimmitha; Dooijes, Dennis; Eichstaedt, Christina A.; Gräf, Stefan; Houweling, Arjan C.; Machado, Rajiv D.; Pandya, Divya; Prapa, Matina; Shaukat, Memoona; Southgate, Laura; Tenorio-Castano, Jair; ClinGen PH VCEP; Chung, Wendy K.; International Consortium for Genetic Studies in Pulmonary Arterial Hypertension (PAH-ICON) at the Pulmonary Vascular Research Institute (PVRI); Medicine, School of Medicine
    Purpose: Pulmonary arterial hypertension (PAH) is a rare, progressive vasculopathy with significant cardiopulmonary morbidity and mortality. Genetic testing is currently recommended for adults diagnosed with heritable, idiopathic, anorexigen-, hereditary hemorrhagic telangiectasia-, and congenital heart disease-associated PAH, PAH with overt features of venous/capillary involvement, and all children diagnosed with PAH. Variants in at least 27 genes have putative evidence for PAH causality. Rigorous assessment of the evidence is needed to inform genetic testing. Methods: An international panel of experts in PAH applied a semi-quantitative scoring system developed by the NIH Clinical Genome Resource to classify the relative strength of evidence supporting PAH gene-disease relationships based on genetic and experimental evidence. Results: Twelve genes (BMPR2, ACVRL1, ATP13A3, CAV1, EIF2AK4, ENG, GDF2, KCNK3, KDR, SMAD9, SOX17, and TBX4) were classified as having definitive evidence and 3 genes (ABCC8, GGCX, and TET2) with moderate evidence. Six genes (AQP1, BMP10, FBLN2, KLF2, KLK1, and PDGFD) were classified as having limited evidence for causal effects of variants. TOPBP1 was classified as having no known PAH relationship. Five genes (BMPR1A, BMPR1B, NOTCH3, SMAD1, and SMAD4) were disputed because of a paucity of genetic evidence over time. Conclusion: We recommend that genetic testing includes all genes with definitive evidence and that caution be taken in the interpretation of variants identified in genes with moderate or limited evidence. Genes with no known evidence for PAH or disputed genes should not be included in genetic testing.