Cells (Dec 2022)
tRNA-like Transcripts from the <i>NEAT1-MALAT1</i> Genomic Region Critically Influence Human Innate Immunity and Macrophage Functions
- Martina Gast,
- Vanasa Nageswaran,
- Andreas W. Kuss,
- Ana Tzvetkova,
- Xiaomin Wang,
- Liliana H. Mochmann,
- Pegah Ramezani Rad,
- Stefan Weiss,
- Stefan Simm,
- Tanja Zeller,
- Henry Voelzke,
- Wolfgang Hoffmann,
- Uwe Völker,
- Stefan B. Felix,
- Marcus Dörr,
- Antje Beling,
- Carsten Skurk,
- David-Manuel Leistner,
- Bernhard H. Rauch,
- Tetsuro Hirose,
- Bettina Heidecker,
- Karin Klingel,
- Shinichi Nakagawa,
- Wolfram C. Poller,
- Filip K. Swirski,
- Arash Haghikia,
- Wolfgang Poller
Affiliations
- Martina Gast
- Department of Cardiology, Campus Benjamin Franklin, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, 12200 Berlin, Germany
- Vanasa Nageswaran
- Department of Cardiology, Campus Benjamin Franklin, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, 12200 Berlin, Germany
- Andreas W. Kuss
- Department of Functional Genomics, Interfaculty Institute of Genetics and Functional Genomics, University Medicine Greifswald, 17475 Greifswald, Germany
- Ana Tzvetkova
- Department of Functional Genomics, Interfaculty Institute of Genetics and Functional Genomics, University Medicine Greifswald, 17475 Greifswald, Germany
- Xiaomin Wang
- Department of Cardiology, Campus Benjamin Franklin, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, 12200 Berlin, Germany
- Liliana H. Mochmann
- Department of Cardiology, Campus Benjamin Franklin, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, 12200 Berlin, Germany
- Pegah Ramezani Rad
- Department of Cardiology, Campus Benjamin Franklin, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, 12200 Berlin, Germany
- Stefan Weiss
- Department of Functional Genomics, Interfaculty Institute of Genetics and Functional Genomics, University Medicine Greifswald, 17475 Greifswald, Germany
- Stefan Simm
- Institute of Bioinformatics, University Medicine Greifswald, 17475 Greifswald, Germany
- Tanja Zeller
- University Center of Cardiovascular Science, University Heart and Vascular Center, 20246 Hamburg, Germany
- Henry Voelzke
- German Center for Cardiovascular Research (DZHK), Site Greifswald, 17487 Greifswald, Germany
- Wolfgang Hoffmann
- German Center for Cardiovascular Research (DZHK), Site Greifswald, 17487 Greifswald, Germany
- Uwe Völker
- Department of Functional Genomics, Interfaculty Institute of Genetics and Functional Genomics, University Medicine Greifswald, 17475 Greifswald, Germany
- Stefan B. Felix
- German Center for Cardiovascular Research (DZHK), Site Greifswald, 17487 Greifswald, Germany
- Marcus Dörr
- German Center for Cardiovascular Research (DZHK), Site Greifswald, 17487 Greifswald, Germany
- Antje Beling
- German Center for Cardiovascular Research (DZHK), Site Berlin, 12200 Berlin, Germany
- Carsten Skurk
- Department of Cardiology, Campus Benjamin Franklin, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, 12200 Berlin, Germany
- David-Manuel Leistner
- Department of Cardiology, Campus Benjamin Franklin, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, 12200 Berlin, Germany
- Bernhard H. Rauch
- German Center for Cardiovascular Research (DZHK), Site Greifswald, 17487 Greifswald, Germany
- Tetsuro Hirose
- Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamadaoka, Suita 565-0871, Japan
- Bettina Heidecker
- Department of Cardiology, Campus Benjamin Franklin, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, 12200 Berlin, Germany
- Karin Klingel
- Institute for Pathology and Neuropathology, Department of Pathology, University Hospital Tübingen, 72076 Tübingen, Germany
- Shinichi Nakagawa
- RNA Biology Laboratory, RIKEN Advanced Research Institute, Wako, Saitama 351-0198, Japan
- Wolfram C. Poller
- Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
- Filip K. Swirski
- Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
- Arash Haghikia
- Department of Cardiology, Campus Benjamin Franklin, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, 12200 Berlin, Germany
- Wolfgang Poller
- Department of Cardiology, Campus Benjamin Franklin, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, 12200 Berlin, Germany
- DOI
- https://doi.org/10.3390/cells11243970
- Journal volume & issue
-
Vol. 11,
no. 24
p. 3970
Abstract
The evolutionary conserved NEAT1-MALAT1 gene cluster generates large noncoding transcripts remaining nuclear, while tRNA-like transcripts (mascRNA, menRNA) enzymatically generated from these precursors translocate to the cytosol. Whereas functions have been assigned to the nuclear transcripts, data on biological functions of the small cytosolic transcripts are sparse. We previously found NEAT1−/− and MALAT1−/− mice to display massive atherosclerosis and vascular inflammation. Here, employing selective targeted disruption of menRNA or mascRNA, we investigate the tRNA-like molecules as critical components of innate immunity. CRISPR-generated human ΔmascRNA and ΔmenRNA monocytes/macrophages display defective innate immune sensing, loss of cytokine control, imbalance of growth/angiogenic factor expression impacting upon angiogenesis, and altered cell–cell interaction systems. Antiviral response, foam cell formation/oxLDL uptake, and M1/M2 polarization are defective in ΔmascRNA/ΔmenRNA macrophages, defining first biological functions of menRNA and describing new functions of mascRNA. menRNA and mascRNA represent novel components of innate immunity arising from the noncoding genome. They appear as prototypes of a new class of noncoding RNAs distinct from others (miRNAs, siRNAs) by biosynthetic pathway and intracellular kinetics. Their NEAT1-MALAT1 region of origin appears as archetype of a functionally highly integrated RNA processing system.
Keywords
