tRNA-like Transcripts from the NEAT1-MALAT1 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

doi:10.3390/cells11243970

tRNA-like Transcripts from the NEAT1-MALAT1 Genomic Region Critically Influence Human Innate Immunity and Macrophage Functions

Cells. 2022 Dec 8;11(24):3970. doi: 10.3390/cells11243970.

Authors

Martina Gast^{1

2}, Vanasa Nageswaran^{1

3}, Andreas W Kuss⁴, Ana Tzvetkova^{4

5}, Xiaomin Wang¹, Liliana H Mochmann¹, Pegah Ramezani Rad¹, Stefan Weiss^{4

6}, Stefan Simm⁵, Tanja Zeller^{7

8}, Henry Voelzke^{6

9}, Wolfgang Hoffmann^{6

9}, Uwe Völker^{4

6}, Stefan B Felix^{6

10}, Marcus Dörr^{6

10}, Antje Beling^{2

11

12}, Carsten Skurk^{1

2}, David-Manuel Leistner^{1

2

12}, Bernhard H Rauch^{6

13

14}, Tetsuro Hirose¹⁵, Bettina Heidecker¹, Karin Klingel¹⁶, Shinichi Nakagawa^{17

18}, Wolfram C Poller^{19

20}, Filip K Swirski^{19

20}, Arash Haghikia^{1

2

12}, Wolfgang Poller^{1

2

21}

Affiliations

¹ 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.
² German Center for Cardiovascular Research (DZHK), Site Berlin, 12200 Berlin, Germany.
³ Institute for Chemistry and Biochemistry, Freie Universität Berlin, 12200 Berlin, Germany.
⁴ Department of Functional Genomics, Interfaculty Institute of Genetics and Functional Genomics, University Medicine Greifswald, 17475 Greifswald, Germany.
⁵ Institute of Bioinformatics, University Medicine Greifswald, 17475 Greifswald, Germany.
⁶ German Center for Cardiovascular Research (DZHK), Site Greifswald, 17487 Greifswald, Germany.
⁷ University Center of Cardiovascular Science, University Heart and Vascular Center, 20246 Hamburg, Germany.
⁸ German Center for Cardiovascular Research (DZHK), Site Hamburg/Lübeck/Kiel, 20246 Hamburg, Germany.
⁹ Institute for Community Medicine, University Medicine Greifswald, 17475 Greifswald, Germany.
¹⁰ Department of Cardiology, University Medicine Greifswald, 17475 Greifswald, Germany.
¹¹ Institute for Biochemistry, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, 10178 Berlin, Germany.
¹² Berlin Institute of Health (BIH), 10178 Berlin, Germany.
¹³ Institute for Pharmacology, University Medicine Greifswald, 17487 Greifswald, Germany.
¹⁴ Department Human Medicine, Section Pharmacology and Toxicology, Carl von Ossietzky Universität, 26129 Oldenburg, Germany.
¹⁵ Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamadaoka, Suita 565-0871, Japan.
¹⁶ Institute for Pathology and Neuropathology, Department of Pathology, University Hospital Tübingen, 72076 Tübingen, Germany.
¹⁷ RNA Biology Laboratory, RIKEN Advanced Research Institute, Wako, Saitama 351-0198, Japan.
¹⁸ Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
¹⁹ Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
²⁰ Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
²¹ Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, 13353 Berlin, Germany.

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: evolutionary genetics; immunogenetics; immunology; innate immunity; noncoding genome; tRNA biology.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Genomics
Humans
Immunity, Innate* / genetics
Immunity, Innate* / immunology
Macrophages* / immunology
RNA, Long Noncoding* / genetics
RNA, Long Noncoding* / immunology
RNA, Transfer* / genetics
RNA, Transfer* / immunology

Substances

RNA, Long Noncoding
RNA, Transfer
NEAT1 long non-coding RNA, human
MALAT1 long non-coding RNA, human

Grants and funding

W.P. and T.Z. received DZHK shared expertise grants B19-006_SE (FKZ 81 × 2,100,257 and FKZ 81 × 2,710,170 ‘Transcriptome analysis of circulating immune cells to improve the assessment of prognosis and the response to novel anti-inflammatory treatments after myocardial infarction’) and B18-004_SE (FKZ 81 × 2,100,253, ‘Functional role and therapeutic potential of the long noncoding RNA NEAT1-MALAT1 genomic region in cardiovascular inflammation control and atheropathogenesis’) from the German Center for Cardiovascular Research (DZHK). T.Z. is supported by the German Center of Cardiovascular Disease (FKZ 81Z0710102; Systems-medicine approaches in cardiovascular disease, partner site project). A.H. received a grant (FKZ 01ZX1906B ‘Systems-medicine of pneumonia-aggravated atherosclerosis’) from the German Federal Ministry of Education and Research (BMBF). A.H. is supported by the Berlin Institute of Health (BIH) Advanced Clinician Scientist program.