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Circular RNAs are a large class of animal RNAs with regulatory potency

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  • Sebastian Memczak

    (Systems Biology of Gene Regulatory Elements, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany)

  • Marvin Jens

    (Systems Biology of Gene Regulatory Elements, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany)

  • Antigoni Elefsinioti

    (Systems Biology of Gene Regulatory Elements, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany)

  • Francesca Torti

    (Systems Biology of Gene Regulatory Elements, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany)

  • Janna Krueger

    (Angiogenesis and Cardiovascular Pathology, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany)

  • Agnieszka Rybak

    (Systems Biology of Gene Regulatory Elements, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany)

  • Luisa Maier

    (Systems Biology of Gene Regulatory Elements, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany)

  • Sebastian D. Mackowiak

    (Systems Biology of Gene Regulatory Elements, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany)

  • Lea H. Gregersen

    (RNA Biology and Post-Transcriptional Regulation, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany)

  • Mathias Munschauer

    (RNA Biology and Post-Transcriptional Regulation, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany)

  • Alexander Loewer

    (Signaling Dynamics in Single Cells, Max-Delbrück-Center for Molecular Medicine)

  • Ulrike Ziebold

    (Systems Biology of Gene Regulatory Elements, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany)

  • Markus Landthaler

    (RNA Biology and Post-Transcriptional Regulation, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany)

  • Christine Kocks

    (Systems Biology of Gene Regulatory Elements, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany)

  • Ferdinand le Noble

    (Angiogenesis and Cardiovascular Pathology, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany)

  • Nikolaus Rajewsky

    (Systems Biology of Gene Regulatory Elements, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany)

Abstract

Circular RNAs (circRNAs) in animals are an enigmatic class of RNA with unknown function. To explore circRNAs systematically, we sequenced and computationally analysed human, mouse and nematode RNA. We detected thousands of well-expressed, stable circRNAs, often showing tissue/developmental-stage-specific expression. Sequence analysis indicated important regulatory functions for circRNAs. We found that a human circRNA, antisense to the cerebellar degeneration-related protein 1 transcript (CDR1as), is densely bound by microRNA (miRNA) effector complexes and harbours 63 conserved binding sites for the ancient miRNA miR-7. Further analyses indicated that CDR1as functions to bind miR-7 in neuronal tissues. Human CDR1as expression in zebrafish impaired midbrain development, similar to knocking down miR-7, suggesting that CDR1as is a miRNA antagonist with a miRNA-binding capacity ten times higher than any other known transcript. Together, our data provide evidence that circRNAs form a large class of post-transcriptional regulators. Numerous circRNAs form by head-to-tail splicing of exons, suggesting previously unrecognized regulatory potential of coding sequences.

Suggested Citation

  • Sebastian Memczak & Marvin Jens & Antigoni Elefsinioti & Francesca Torti & Janna Krueger & Agnieszka Rybak & Luisa Maier & Sebastian D. Mackowiak & Lea H. Gregersen & Mathias Munschauer & Alexander Lo, 2013. "Circular RNAs are a large class of animal RNAs with regulatory potency," Nature, Nature, vol. 495(7441), pages 333-338, March.
  • Handle: RePEc:nat:nature:v:495:y:2013:i:7441:d:10.1038_nature11928
    DOI: 10.1038/nature11928
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    Cited by:

    1. Jian Zhong & Xujia Wu & Yixin Gao & Junju Chen & Maolei Zhang & Huangkai Zhou & Jia Yang & Feizhe Xiao & Xuesong Yang & Nunu Huang & Haoyue Qi & Xiuxing Wang & Fan Bai & Yu Shi & Nu Zhang, 2023. "Circular RNA encoded MET variant promotes glioblastoma tumorigenesis," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Nana Xu & Jiebang Jiang & Fei Jiang & Guokai Dong & Li Meng & Meng Wang & Jing Chen & Cong Li & Yongping Shi & Sisi He & Rongpeng Li, 2024. "CircCDC42-encoded CDC42-165aa regulates macrophage pyroptosis in Klebsiella pneumoniae infection through Pyrin inflammasome activation," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    3. Zhenzhen Chen & Qiankun He & Tiankun Lu & Jiayi Wu & Gaoli Shi & Luyun He & Hong Zong & Benyu Liu & Pingping Zhu, 2023. "mcPGK1-dependent mitochondrial import of PGK1 promotes metabolic reprogramming and self-renewal of liver TICs," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    4. Federica Conte & Giulia Fiscon & Matteo Chiara & Teresa Colombo & Lorenzo Farina & Paola Paci, 2017. "Role of the long non-coding RNA PVT1 in the dysregulation of the ceRNA-ceRNA network in human breast cancer," PLOS ONE, Public Library of Science, vol. 12(2), pages 1-22, February.
    5. Junliang Yin & Xiaowen Han & Yongxing Zhu & Zhengwu Fang & Derong Gao & Dongfang Ma, 2022. "Transcriptome Profiles of Circular RNAs in Common Wheat during Fusarium Head Blight Disease," Data, MDPI, vol. 7(9), pages 1-8, August.
    6. Ting-Ting He & Yun-Fan Xu & Xiang Li & Xia Wang & Jie-Yu Li & Dan Ou-Yang & Han-Sen Cheng & Hao-Yang Li & Jia Qin & Yu Huang & Hai-Yan Wang, 2023. "A linear and circular dual-conformation noncoding RNA involved in oxidative stress tolerance in Bacillus altitudinis," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    7. Yue Liu & Yue Yang & Chenying Xu & Jianxing Liu & Jiale Chen & Guoqing Li & Bin Huang & Yi Pan & Yanfeng Zhang & Qiong Wei & Stephen J. Pandol & Fangfang Zhang & Ling Li & Liang Jin, 2023. "Circular RNA circGlis3 protects against islet β-cell dysfunction and apoptosis in obesity," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    8. Amir Bar & Liron Argaman & Michal Eldar & Hanah Margalit, 2023. "TRS: a method for determining transcript termini from RNAtag-seq sequencing data," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    9. Sen Ma & Xiaochun Xu & Xiaolong Wang & Yuxin Yang & Yinghua Shi & Yulin Chen, 2022. "Comprehensive Profiling of Circular RNAs in Goat Dermal Papilla Cells and Prediction of Their Modulatory Roles in Hair Growth," Agriculture, MDPI, vol. 12(9), pages 1-14, August.
    10. Shaomin Yang & Di Cao & Dabbu Kumar Jaijyan & Mei Wang & Jian Liu & Ruth Cruz-cosme & Songbin Wu & Jiabin Huang & Mulan Zeng & Xiaolian Liu & Wuping Sun & Donglin Xiong & Qiyi Tang & Lizu Xiao & Hua Z, 2024. "Identification and characterization of Varicella Zoster Virus circular RNA in lytic infection," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    11. Xianjun Dong & Yunfei Bai & Zhixiang Liao & David Gritsch & Xiaoli Liu & Tao Wang & Rebeca Borges-Monroy & Alyssa Ehrlich & Geidy E. Serrano & Mel B. Feany & Thomas G. Beach & Clemens R. Scherzer, 2023. "Circular RNAs in the human brain are tailored to neuron identity and neuropsychiatric disease," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    12. Yu Dong & Qian Gao & Yong Chen & Zhao Zhang & Yanhua Du & Yuan Liu & Guangxiong Zhang & Shengli Li & Gaoyang Wang & Xiang Chen & Hong Liu & Leng Han & Youqiong Ye, 2023. "Identification of CircRNA signature associated with tumor immune infiltration to predict therapeutic efficacy of immunotherapy," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    13. Bin Li & Wen-Wu Bai & Tao Guo & Zhen-Yu Tang & Xue-Jiao Jing & Ti-Chao Shan & Sen Yin & Ying Li & Fu Wang & Mo-Li Zhu & Jun-Xiu Lu & Yong-Ping Bai & Bo Dong & Peng Li & Shuang-Xi Wang, 2024. "Statins improve cardiac endothelial function to prevent heart failure with preserved ejection fraction through upregulating circRNA-RBCK1," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    14. Steffen Fuchs & Clara Danßmann & Filippos Klironomos & Annika Winkler & Jörg Fallmann & Louisa-Marie Kruetzfeldt & Annabell Szymansky & Julian Naderi & Stephan H. Bernhart & Laura Grunewald & Konstant, 2023. "Defining the landscape of circular RNAs in neuroblastoma unveils a global suppressive function of MYCN," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    15. Maya Ron & Igor Ulitsky, 2022. "Context-specific effects of sequence elements on subcellular localization of linear and circular RNAs," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    16. Xiaojuan Fan & Yun Yang & Chuyun Chen & Zefeng Wang, 2022. "Pervasive translation of circular RNAs driven by short IRES-like elements," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    17. Mateja Rybiczka-Tešulov & Oxana Garritsen & Morten T. Venø & Laura Wieg & Roland van Dijk & Karim Rahimi & Andreia Gomes-Duarte & Marina de Wit & Lieke L. Haar & Lars Michels & Nicky C. H. van Kronenb, 2024. "Circular RNAs regulate neuron size and migration of midbrain dopamine neurons during development," Nature Communications, Nature, vol. 15(1), pages 1-23, December.
    18. Ke Li & Jiawei Guo & Yue Ming & Shuang Chen & Tingting Zhang & Hulin Ma & Xin Fu & Jin Wang & Wenrong Liu & Yong Peng, 2023. "A circular RNA activated by TGFβ promotes tumor metastasis through enhancing IGF2BP3-mediated PDPN mRNA stability," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    19. Roberta Piras & Emily Y. Ko & Connor Barrett & Marco Simone & Xianzhi Lin & Marina T. Broz & Fernando H. G. Tessaro & Mireia Castillo-Martin & Carlos Cordon-Cardo & Helen S. Goodridge & Dolores Vizio , 2022. "circCsnk1g3- and circAnkib1-regulated interferon responses in sarcoma promote tumorigenesis by shaping the immune microenvironment," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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