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Endogenous antisense RNA curbs CD39 expression in Crohn’s disease

Author

Listed:
  • Rasika P. Harshe

    (Beth Israel Deaconess Medical Center, Harvard Medical School)

  • Anyan Xie

    (Beth Israel Deaconess Medical Center, Harvard Medical School)

  • Marta Vuerich

    (Beth Israel Deaconess Medical Center, Harvard Medical School)

  • Luiza Abrahão Frank

    (Beth Israel Deaconess Medical Center, Harvard Medical School)

  • Barbora Gromova

    (Beth Israel Deaconess Medical Center, Harvard Medical School
    Comenius University)

  • Haohai Zhang

    (Beth Israel Deaconess Medical Center, Harvard Medical School)

  • Rene’ J. Robles

    (Beth Israel Deaconess Medical Center, Harvard Medical School)

  • Samiran Mukherjee

    (Beth Israel Deaconess Medical Center, Harvard Medical School)

  • Eva Csizmadia

    (Beth Israel Deaconess Medical Center, Harvard Medical School)

  • Efi Kokkotou

    (Beth Israel Deaconess Medical Center, Harvard Medical School)

  • Adam S. Cheifetz

    (Beth Israel Deaconess Medical Center, Harvard Medical School)

  • Alan C. Moss

    (Beth Israel Deaconess Medical Center, Harvard Medical School)

  • Satya K. Kota

    (Harvard School of Dental Medicine)

  • Simon C. Robson

    (Beth Israel Deaconess Medical Center, Harvard Medical School
    Beth Israel Deaconess Medical Center, Harvard Medical School)

  • Maria Serena Longhi

    (Beth Israel Deaconess Medical Center, Harvard Medical School)

Abstract

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.

Suggested Citation

  • Rasika P. Harshe & Anyan Xie & Marta Vuerich & Luiza Abrahão Frank & Barbora Gromova & Haohai Zhang & Rene’ J. Robles & Samiran Mukherjee & Eva Csizmadia & Efi Kokkotou & Adam S. Cheifetz & Alan C. Mo, 2020. "Endogenous antisense RNA curbs CD39 expression in Crohn’s disease," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-19692-y
    DOI: 10.1038/s41467-020-19692-y
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