Endogenous antisense RNA curbs CD39 expression in Crohn’s disease

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. Moss, Satya K. Kota, Simon C. Robson and Maria Serena Longhi ()
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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
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
Maria Serena Longhi: Beth Israel Deaconess Medical Center, Harvard Medical School

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-19692-y

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