4.8 Article

Endogenous antisense RNA curbs CD39 expression in Crohn's disease

Journal

NATURE COMMUNICATIONS
Volume 11, Issue 1, Pages -

Publisher

NATURE RESEARCH
DOI: 10.1038/s41467-020-19692-y

Keywords

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Funding

  1. National Institute of Health [R01 DK108894, R21 CA164970]
  2. AASLD Pilot Research Award
  3. Department of Anesthesia, Critical Care Pain Medicine
  4. Department of Defense Award [W81XWH-16-0464]
  5. CAPES, Brazil [88881.171857/2018-01]
  6. Slovak Research and Development Agency [APVV-17-0505]
  7. Scholarship Dr. Ludmily Sedlarovey-Rabanovej
  8. Nadacia Tatra banky

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CD39 is an ectonucleotidase that initiates conversion of extracellular nucleotides into immunosuppressive adenosine. CD39 is expressed by regulatory T (Treg)-cells, where it mediates immunosuppression, and by a subset of T-helper (Th) 17-cells, where it limits pathogenicity. CD39 is regulated via single-nucleotide-polymorphisms and upon activation of aryl-hydrocarbon-receptor and oxygen-mediated pathways. Here we report a mechanism of CD39 regulation that relies on the presence of an endogenous antisense RNA, transcribed from the 3-end of the human CD39/ENTPD1 gene. CD39-specific antisense is increased in Treg and Th17-cells of Crohn's disease patients over controls. It largely localizes in the cell nucleus and regulates CD39 by interacting with nucleolin and heterogeneous-nuclear-ribonucleoprotein-A1. Antisense silencing results in CD39 upregulation in vitro and amelioration of disease activity in a trinitro-benzene-sulfonic-acid model of colitis in humanized NOD/scid/gamma mice. Inhibition/blockade of antisense might represent a therapeutic strategy to restore CD39 along with immunohomeostasis in Crohn's disease. CD39 is an ectonucleotidase associated with immunoregulatory function. Here authors show regulation of CD39 expression by an endogenous antisense RNA moiety transcribed from the 3' end of CD39/ENTPD1 which when itself is silenced results in amelioration of pathology in an animal model of colitis.

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