An expressed pseudogene regulates the messenger-RNA stability of its homologous coding gene

Nature volume 423, pages91–96(2003)Cite this article

An Addendum to this article was published on 06 November 2003

Abstract

A pseudogene is a gene copy that does not produce a functional, full-length protein1. The human genome is estimated to contain up to 20,000 pseudogenes2,3. Although much effort has been devoted to understanding the function of pseudogenes, their biological roles remain largely unknown. Here we report the role of an expressed pseudogene—regulation of messenger-RNA stability—in a transgene-insertion mouse mutant exhibiting polycystic kidneys and bone deformity. The transgene was integrated into the vicinity of the expressing pseudogene of Makorin1, called Makorin1-p1. This insertion reduced transcription of Makorin1-p1, resulting in destabilization of Makorin1 mRNA in trans by way of a cis-acting RNA decay element within the 5′ region of Makorin1 that is homologous between Makorin1 and Makorin1-p1. Either Makorin1 or Makorin1-p1 transgenes could rescue these phenotypes. Our findings demonstrate a specific regulatory role of an expressed pseudogene, and point to the functional significance of non-coding RNAs.

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Figure 1: Analysis of mutant phenotypes and genetic study.
Figure 2: Identification of the mutated gene and expression profile.
Figure 3: Demonstration of stabilization of Makorin1 mRNA by Makorin1-p1 mRNA in trans.
Figure 4: Rescue of the mutant phenotypes by exogenous Makorin1-p1 or Makorin1 cDNA transgene expression.

References

  1. 1

    Vanin, E. F. Processed pseudogene: Characteristics and evolution. Annu. Rev. Genet. 19, 253–272 (1985)

    CAS  Article  Google Scholar 

  2. 2

    Goncalves, I., Duret, L. & Mouchiroud, D. Nature and structure of human genes that generate retropseudogenes. Genome Res. 10, 672–678 (2000)

    CAS  Article  Google Scholar 

  3. 3

    Harrison, P. M. et al. Molecular fossils in the human genome: identification and analysis of the pseudogenes in chromosomes 21 and 22. Genome Res. 12, 272–280 (2002)

    CAS  Article  Google Scholar 

  4. 4

    Nagai, Y. et al. Role of interleukin-6 in uncoupling of bone in vitro in a human squamous carcinoma coproducing parathyroid hormone-related peptide and interleukin-6. J. Bone Miner. Res. 13, 664–671 (1998)

    CAS  Article  Google Scholar 

  5. 5

    Gray, T. A. et al. The ancient source of a distinct gene family encoding proteins featuring RING and C (3) H zinc-finger motifs with abundant expression in developing brain and nervous system. Genomics 25, 14430–14435 (2000)

    Google Scholar 

  6. 6

    Greally, J. M. et al. Conserved characteristics of heterochromatin-forming DNA at the 15q11-q13 imprinting center. Proc. Natl Acad. Sci. USA 25, 14430–14435 (1999)

    ADS  Article  Google Scholar 

  7. 7

    Niwa, H., Yamamura, K. & Miyazaki, J. Efficient selection for high-expression transfectants with a novel eukaryotic vector. Gene 108, 193–200 (1991)

    CAS  Article  Google Scholar 

  8. 8

    Mighell, A. J., Smith, N. R., Robinson, P. A. & Markham, A. F. Vertebrate pseudogenes. FEBS Lett. 468, 109–114 (2000)

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank Y. Sugimoto, T. Matsukawa, T. Harigaya, N. Deguchi, Y. Obata, K. Moriwaki and M. Muramatsu for support; T. Itoh, T. Matsumoto, S. Sasaki, M. Ishida and Y. Yamauchi for technical support; P. Schedl for providing Sxl cDNA; T. Shiroishi for providing M. molossinus; J.-i. Hata for comments on pathology; G. G. Germino for suggestions and encouragement; S. Okumura, K. Hagiwara, N. Tominaga and M. Suzuki for mouse breeding; and S. Kunita, N. Kajiwara, K. Furuya, M. Hirose, H. Sanno and Y. Suzuki for generating transgenic mice. This work was supported by PRESTO, Japan Science and Technology Corporation (S.H), PROBRAIN (S.T), and Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, and Technology (A.Y.).

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Affiliations

  1. Division of Neuroscience, Research Center for Genomic Medicine, Saitama Medical School Yamane 1397-1, Saitama, 350-1241, Hidaka City, Japan

    Shinji Hirotsune & Noriyuki Yoshida

  2. PRESTO, Japan Science and Technology Corporation, Hon-cho 4-1-8, Kawaguchi, Saitama, Japan

    Shinji Hirotsune

  3. Genetic Disease Research Branch, National Human Genome Research Institute, NIH, Bldg 49, Room 4C80 49, Convent Drive, Bethesda, Maryland, 20892, USA

    Amy Chen, Lisa Garrett & Anthony Wynshaw-Boris

  4. Institute of Basic Medical Sciences and Laboratory Animal Resource Center, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan

    Fumihiro Sugiyama, Satoru Takahashi & Ken-ichi Yagami

  5. Departments of Pediatrics and Medicine, UCSD Cancer Center, University of California, San Diego School of Medicine, 9500 Gilman Drive, Mailstop 0627, La Jolla, California, 92093-0627, USA

    Anthony Wynshaw-Boris

  6. Experimental Animal Division, Department of Biological Systems, BioResource Center, RIKEN Tsukuba Institute, 3-1-1 Koyadai, Tsukuba, Ibaraki, 305-0074, Japan

    Atsushi Yoshiki

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  1. Shinji Hirotsune
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  2. Noriyuki Yoshida
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  3. Amy Chen
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  4. Lisa Garrett
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  7. Ken-ichi Yagami
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  8. Anthony Wynshaw-Boris
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  9. Atsushi Yoshiki
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Correspondence to Shinji Hirotsune.

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Hirotsune, S., Yoshida, N., Chen, A. et al. An expressed pseudogene regulates the messenger-RNA stability of its homologous coding gene. Nature 423, 91–96 (2003). https://doi.org/10.1038/nature01535

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