Circular non-coding RNA ANRIL modulates ribosomal RNA maturation and atherosclerosis in humans

Lesca M Holdt; Anika Stahringer; Kristina Sass; Garwin Pichler; Nils A Kulak; Wolfgang Wilfert; Alexander Kohlmaier; Andreas Herbst; Bernd H Northoff; Alexandros Nicolaou; Gabor Gäbel; Frank Beutner; Markus Scholz; Joachim Thiery; Kiran Musunuru; Knut Krohn; Matthias Mann; Daniel Teupser

doi:10.1038/ncomms12429

Circular non-coding RNA ANRIL modulates ribosomal RNA maturation and atherosclerosis in humans

Lesca M Holdt, Anika Stahringer, Kristina Sass, Garwin Pichler, Nils A Kulak, Wolfgang Wilfert, Alexander Kohlmaier, Andreas Herbst, Bernd H Northoff, Alexandros Nicolaou, Gabor Gäbel, Frank Beutner, Markus Scholz, Joachim Thiery, Kiran Musunuru, Knut Krohn, Matthias Mann, Daniel Teupser

482 Citationer (Scopus)

Abstract

Circular RNAs (circRNAs) are broadly expressed in eukaryotic cells, but their molecular mechanism in human disease remains obscure. Here we show that circular antisense non-coding RNA in the INK4 locus (circANRIL), which is transcribed at a locus of atherosclerotic cardiovascular disease on chromosome 9p21, confers atheroprotection by controlling ribosomal RNA (rRNA) maturation and modulating pathways of atherogenesis. CircANRIL binds to pescadillo homologue 1 (PES1), an essential 60S-preribosomal assembly factor, thereby impairing exonuclease-mediated pre-rRNA processing and ribosome biogenesis in vascular smooth muscle cells and macrophages. As a consequence, circANRIL induces nucleolar stress and p53 activation, resulting in the induction of apoptosis and inhibition of proliferation, which are key cell functions in atherosclerosis. Collectively, these findings identify circANRIL as a prototype of a circRNA regulating ribosome biogenesis and conferring atheroprotection, thereby showing that circularization of long non-coding RNAs may alter RNA function and protect from human disease.

Originalsprog	Engelsk
Tidsskrift	Nature Communications
Vol/bind	7
Sider (fra-til)	12429
ISSN	2041-1723
DOI	https://doi.org/10.1038/ncomms12429
Status	Udgivet - 19 aug. 2016
Udgivet eksternt	Ja

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10.1038/ncomms12429

ncomms12429.pdfForlagets udgivne version, 1,51 MBLicens: CC BY

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Holdt, L. M., Stahringer, A., Sass, K., Pichler, G., Kulak, N. A., Wilfert, W., Kohlmaier, A., Herbst, A., Northoff, B. H., Nicolaou, A., Gäbel, G., Beutner, F., Scholz, M., Thiery, J., Musunuru, K., Krohn, K., Mann, M., & Teupser, D. (2016). Circular non-coding RNA ANRIL modulates ribosomal RNA maturation and atherosclerosis in humans. Nature Communications, 7, 12429. https://doi.org/10.1038/ncomms12429

Holdt, LM, Stahringer, A, Sass, K, Pichler, G, Kulak, NA, Wilfert, W, Kohlmaier, A, Herbst, A, Northoff, BH, Nicolaou, A, Gäbel, G, Beutner, F, Scholz, M, Thiery, J, Musunuru, K, Krohn, K, Mann, M & Teupser, D 2016, 'Circular non-coding RNA ANRIL modulates ribosomal RNA maturation and atherosclerosis in humans', Nature Communications, bind 7, s. 12429. https://doi.org/10.1038/ncomms12429

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title = "Circular non-coding RNA ANRIL modulates ribosomal RNA maturation and atherosclerosis in humans",

abstract = "Circular RNAs (circRNAs) are broadly expressed in eukaryotic cells, but their molecular mechanism in human disease remains obscure. Here we show that circular antisense non-coding RNA in the INK4 locus (circANRIL), which is transcribed at a locus of atherosclerotic cardiovascular disease on chromosome 9p21, confers atheroprotection by controlling ribosomal RNA (rRNA) maturation and modulating pathways of atherogenesis. CircANRIL binds to pescadillo homologue 1 (PES1), an essential 60S-preribosomal assembly factor, thereby impairing exonuclease-mediated pre-rRNA processing and ribosome biogenesis in vascular smooth muscle cells and macrophages. As a consequence, circANRIL induces nucleolar stress and p53 activation, resulting in the induction of apoptosis and inhibition of proliferation, which are key cell functions in atherosclerosis. Collectively, these findings identify circANRIL as a prototype of a circRNA regulating ribosome biogenesis and conferring atheroprotection, thereby showing that circularization of long non-coding RNAs may alter RNA function and protect from human disease.",

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T1 - Circular non-coding RNA ANRIL modulates ribosomal RNA maturation and atherosclerosis in humans

AU - Holdt, Lesca M

AU - Stahringer, Anika

AU - Sass, Kristina

AU - Pichler, Garwin

AU - Kulak, Nils A

AU - Wilfert, Wolfgang

AU - Kohlmaier, Alexander

AU - Herbst, Andreas

AU - Northoff, Bernd H

AU - Nicolaou, Alexandros

AU - Gäbel, Gabor

AU - Beutner, Frank

AU - Scholz, Markus

AU - Thiery, Joachim

AU - Musunuru, Kiran

AU - Krohn, Knut

AU - Mann, Matthias

AU - Teupser, Daniel

PY - 2016/8/19

Y1 - 2016/8/19

N2 - Circular RNAs (circRNAs) are broadly expressed in eukaryotic cells, but their molecular mechanism in human disease remains obscure. Here we show that circular antisense non-coding RNA in the INK4 locus (circANRIL), which is transcribed at a locus of atherosclerotic cardiovascular disease on chromosome 9p21, confers atheroprotection by controlling ribosomal RNA (rRNA) maturation and modulating pathways of atherogenesis. CircANRIL binds to pescadillo homologue 1 (PES1), an essential 60S-preribosomal assembly factor, thereby impairing exonuclease-mediated pre-rRNA processing and ribosome biogenesis in vascular smooth muscle cells and macrophages. As a consequence, circANRIL induces nucleolar stress and p53 activation, resulting in the induction of apoptosis and inhibition of proliferation, which are key cell functions in atherosclerosis. Collectively, these findings identify circANRIL as a prototype of a circRNA regulating ribosome biogenesis and conferring atheroprotection, thereby showing that circularization of long non-coding RNAs may alter RNA function and protect from human disease.

AB - Circular RNAs (circRNAs) are broadly expressed in eukaryotic cells, but their molecular mechanism in human disease remains obscure. Here we show that circular antisense non-coding RNA in the INK4 locus (circANRIL), which is transcribed at a locus of atherosclerotic cardiovascular disease on chromosome 9p21, confers atheroprotection by controlling ribosomal RNA (rRNA) maturation and modulating pathways of atherogenesis. CircANRIL binds to pescadillo homologue 1 (PES1), an essential 60S-preribosomal assembly factor, thereby impairing exonuclease-mediated pre-rRNA processing and ribosome biogenesis in vascular smooth muscle cells and macrophages. As a consequence, circANRIL induces nucleolar stress and p53 activation, resulting in the induction of apoptosis and inhibition of proliferation, which are key cell functions in atherosclerosis. Collectively, these findings identify circANRIL as a prototype of a circRNA regulating ribosome biogenesis and conferring atheroprotection, thereby showing that circularization of long non-coding RNAs may alter RNA function and protect from human disease.

KW - Journal Article

U2 - 10.1038/ncomms12429

DO - 10.1038/ncomms12429

M3 - Journal article

C2 - 27539542

SN - 2041-1723

VL - 7

SP - 12429

JO - Nature Communications

JF - Nature Communications

ER -

Circular non-coding RNA ANRIL modulates ribosomal RNA maturation and atherosclerosis in humans

Abstract

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