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

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.

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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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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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