Browsing by Author "Parikh, Victoria N."

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    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.
  • Thumbnail Image
    Item
    Pathologic gene network rewiring implicates PPP1R3A as a central regulator in pressure overload heart failure
    (Springer Nature, 2019-06-24) Cordero, Pablo; Parikh, Victoria N.; Chin, Elizabeth T.; Erbilgin, Ayca; Gloudemans, Michael J.; Shang, Ching; Huang, Yong; Chang, Alex C.; Smith, Kevin S.; Dewey, Frederick; Zaleta, Kathia; Morley, Michael; Brandimarto, Jeff; Glazer, Nicole; Waggott, Daryl; Pavlovic, Aleksandra; Zhao, Mingming; Moravec, Christine S.; Tang, W. H. Wilson; Skreen, Jamie; Malloy, Christine; Hannenhalli, Sridhar; Li, Hongzhe; Ritter, Scott; Li, Mingyao; Bernstein, Daniel; Connolly, Andrew; Hakonarson, Hakon; Lusis, Aldons J.; Margulies, Kenneth B.; Depaoli-Roach, Anna A.; Montgomery, Stephen B.; Wheeler, Matthew T.; Cappola, Thomas; Ashley, Euan A.; Biochemistry and Molecular Biology, School of Medicine
    Heart failure is a leading cause of mortality, yet our understanding of the genetic interactions underlying this disease remains incomplete. Here, we harvest 1352 healthy and failing human hearts directly from transplant center operating rooms, and obtain genome-wide genotyping and gene expression measurements for a subset of 313. We build failing and non-failing cardiac regulatory gene networks, revealing important regulators and cardiac expression quantitative trait loci (eQTLs). PPP1R3A emerges as a regulator whose network connectivity changes significantly between health and disease. RNA sequencing after PPP1R3A knockdown validates network-based predictions, and highlights metabolic pathway regulation associated with increased cardiomyocyte size and perturbed respiratory metabolism. Mice lacking PPP1R3A are protected against pressure-overload heart failure. We present a global gene interaction map of the human heart failure transition, identify previously unreported cardiac eQTLs, and demonstrate the discovery potential of disease-specific networks through the description of PPP1R3A as a central regulator in heart failure.