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A methyl transferase links the circadian clock to the regulation of alternative splicing

Nature volume 468, pages 112–116 (2010)Cite this article

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Abstract

Circadian rhythms allow organisms to time biological processes to the most appropriate phases of the day–night cycle1. Post-transcriptional regulation is emerging as an important component of circadian networks2,3,4,5,6, but the molecular mechanisms linking the circadian clock to the control of RNA processing are largely unknown. Here we show that PROTEIN ARGININE METHYL TRANSFERASE 5 (PRMT5), which transfers methyl groups to arginine residues present in histones7 and Sm spliceosomal proteins8,9, links the circadian clock to the control of alternative splicing in plants. Mutations in PRMT5 impair several circadian rhythms in Arabidopsis thaliana and this phenotype is caused, at least in part, by a strong alteration in alternative splicing of the core-clock gene PSEUDO RESPONSE REGULATOR 9 (PRR9). Furthermore, genome-wide studies show that PRMT5 contributes to the regulation of many pre-messenger-RNA splicing events, probably by modulating 5′-splice-site recognition. PRMT5 expression shows daily and circadian oscillations, and this contributes to the mediation of the circadian regulation of expression and alternative splicing of a subset of genes. Circadian rhythms in locomotor activity are also disrupted in dart5-1, a mutant affected in the Drosophila melanogaster PRMT5 homologue, and this is associated with alterations in splicing of the core-clock gene period and several clock-associated genes. Our results demonstrate a key role for PRMT5 in the regulation of alternative splicing and indicate that the interplay between the circadian clock and the regulation of alternative splicing by PRMT5 constitutes a common mechanism that helps organisms to synchronize physiological processes with daily changes in environmental conditions.

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Figure 1: A role for PRMT5 in the circadian system of Arabidopsis.
Figure 2: PRMT5 affects expression and alternative splicing of the clock gene PRR9.
Figure 3: Genome-wide analysis of pre-mRNA splicing in Arabidopsis prmt5 mutants.
Figure 4: PRMT5 regulates circadian rhythms and pre-mRNA splicing in Drosophila.

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Gene Expression Omnibus

Data deposits

The data discussed in this publication have been deposited in the National Center for Biotechnology Information Gene Expression Omnibus and are accessible through GEO Series accession number GSE18808 (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE18808).

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Acknowledgements

We thank E. M. Farré and S. L. Harmer for seeds; J. J. Casal and S. Mora-García for critical reading of the manuscript; the laboratories of A.R.K. and M.J.Y. for discussions; J. Fuller and P. Tondi for technical assistance. This work was supported by grants from the Fundación Antorchas, the Agencia Nacional de Promoción de Ciencia y Tecnología of Argentina, the Consejo Nacional de Investigaciones Científicas y Técnicas of Argentina and the University of Buenos Aires to M.J.Y. and A.R.K., and from the European Union Network of Excellence on Alternative Splicing (EURASNET) to A.R.K. and J.W.S.B. M.J.Y. and A.R.K. are Howard Hughes Medical Institute international research scholars. P.M.’s laboratory is supported by a Ministerio de Educación y Ciencia grant, the European Young Investigator Awards and the EMBO Young Investigator Awards; M.F.C.’s laboratory is supported by Proyecto de Investigación Científica y Tecnológica 2006-1249.

Author information

Author notes

  1. Sabrina E. Sanchez and Ezequiel Petrillo: These authors contributed equally to this work.

Authors and Affiliations

  1. IFEVA, Facultad de Agronomía, UBA-CONICET, Buenos Aires, C1417DSE, Argentina

    Sabrina E. Sanchez, Matias L. Rugnone, C. Esteban Hernando & Marcelo J. Yanovsky

  2. IFIBYNE, FCEyN, UBA-CONICET, Buenos Aires, C1428EGA, Argentina

    Ezequiel Petrillo, Micaela A. Godoy Herz & Alberto R. Kornblihtt

  3. Fundación Instituto Leloir, IIBBA-CONICET, Buenos Aires, C1405BWE, Argentina

    Esteban J. Beckwith, Ana Depetris-Chauvin, Pablo D. Cerdán, M. Fernanda Ceriani & Marcelo J. Yanovsky

  4. Department of Ecology & Evolution, University of Chicago, Chicago, 60637, Illinois, USA

    Xu Zhang & Justin O. Borevitz

  5. Centre for Research in Agricultural Genomics (CRAG), Consortium CSIC-IRTA-UAB, Barcelona, 08034, Spain

    Juan C. Cuevas & Paloma Mas

  6. Genetics Programme, SCRI, Invergowrie, Dundee, DD2 5DA, UK

    Craig G. Simpson & John W. S. Brown

  7. Division of Plant Sciences, University of Dundee at SCRI, Dundee, DD2 5DA, UK

    John W. S. Brown

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Contributions

S.E.S. and E.P. contributed equally to this work and performed most of the experiments in this study, with technical assistance from M.L.R., C.E.H., M.A.G.H. and P.D.C. J.C.C. and P.M. conducted bioluminescence and chromatin immunoprecipation assays. E.J.B. and A.D.C. performed locomotor activity assays, RNA extractions and immunostaining experiments in Drosophila. E.P., C.G.S. and J.W.S.B. performed high-resolution RT–PCR experiments. X.Z. and J.O.B. analysed tiling array data. S.E.S., E.P., M.F.C., A.R.K. and M.J.Y. provided input in the preparation of the manuscript, and S.E.S., E.P. and M.J.Y. wrote the paper.

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Correspondence to Marcelo J. Yanovsky.

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Sanchez, S., Petrillo, E., Beckwith, E. et al. A methyl transferase links the circadian clock to the regulation of alternative splicing. Nature 468, 112–116 (2010). https://doi.org/10.1038/nature09470

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