Browsing by Author "Tiwari, Vijay K."

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    Mapping the daily rhythmic transcriptome in the diabetic retina
    (Elsevier, 2024) Silk, Ryan P.; Winter, Hanagh R.; Dkhissi-Benyahya, Ouria; Evans-Molina, Carmella; Stitt, Alan W.; Tiwari, Vijay K.; Simpson, David A.; Beli, Eleni; Medicine, School of Medicine
    Retinal function changes dramatically from day to night, yet clinical diagnosis, treatments, and experimental sampling occur during the day. To begin to address this gap in our understanding of disease pathobiology, this study investigates whether diabetes affects the retina's daily rhythm of gene expression. Diabetic, Ins2Akita/J mice, and non-diabetic littermates were kept under a 12 h:12 h light/dark cycle until 4 months of age. mRNA sequencing was conducted in retinas collected every 4 h throughout the 24 hr light/dark cycle. Computational approaches were used to detect rhythmicity, predict acrophase, identify differential rhythmic patterns, analyze phase set enrichment, and predict upstream regulators. The retinal transcriptome exhibited a tightly regulated rhythmic expression with a clear 12-hr transcriptional axis. Day-peaking genes were enriched for DNA repair, RNA splicing, and ribosomal protein synthesis, night-peaking genes for metabolic processes and growth factor signaling. Although the 12-hr transcriptional axis is retained in the diabetic retina, it is phase advanced for some genes. Upstream regulator analysis for the phase-shifted genes identified oxygen-sensing mechanisms and HIF1alpha, but not the circadian clock, which remained in phase with the light/dark cycle. We propose a model in which, early in diabetes, the retina is subjected to an internal desynchrony with the circadian clock and its outputs are still light-entrained whereas metabolic pathways related to neuronal dysfunction and hypoxia are phase advanced. Further studies are now required to evaluate the chronic implications of such desynchronization on the development of diabetic retinopathy.
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    ZNFX1 is a Novel Master Regulator in Epigenetically-induced Pathogen Mimicry and Inflammasome Signaling in Cancer
    (bioRxiv, 2024-10-21) Stojanovic, Lora; Abbotts, Rachel; Tripathi, Kaushlendra; Coon, Collin M.; Rajendran, Saranya; Farid, Elnaz Abbasi; Hostetter, Galen; Guarnieri, Joseph W.; Wallace, Douglas C.; Liu, Sheng; Wan, Jun; Calendo, Gennaro; Marker, Rebecca; Gohari, Zahra; Inayatullah, Mohammed M. A.; Tiwari, Vijay K.; Kader, Tanjina; Santagata, Sandro; Drapkin, Ronny; Kommoss, Stefan; Pfisterer, Jacobus; Konecny, Gottfried E.; Coopergard, Ryan; Issa, Jean-Pierre; Winterhoff, Boris J. N.; Topper, Michael J.; Sandusky, George E.; Miller, Kathy D.; Baylin, Stephen B.; Nephew, Kenneth P.; Rassool, Feyruz V.; Medical and Molecular Genetics, School of Medicine
    DNA methyltransferase and poly(ADP-ribose) polymerase inhibitors (DNMTis, PARPis) induce a stimulator of interferon (IFN) genes (STING)-dependent pathogen mimicry response (PMR) in ovarian (OC) and other cancers. We now show that combining DNMTis and PARPis upregulates expression of a little-studied nucleic-acid sensor, NFX1-type zinc finger-containing 1 protein (ZNFX1). We demonstrate that ZNFX1 is a novel master regulator for PMR induction in mitochondria, serving as a gateway for STING-dependent PMR. In patient OC databases, high ZNFX1 expression levels correlate with advanced stage disease. ZNFX1 expression alone significantly correlates with an increase in overall survival in a phase 3 trial for therapy-resistant OC patients receiving bevacizumab in combination with chemotherapy. In correlative RNA-seq data, inflammasome signaling through ZNFX1 correlates with abnormal vasculogenesis. ZNFX1 controls PMR signaling through the mitochondria and may serve as a biomarker to facilitate offering personalized therapy in OC patients, highlighting the strong translational significance of our findings.