Argonaute proteins couple chromatin silencing to alternative splicing

Maya Ameyar-Zazoua, Christophe Rachez, Mouloud Souidi, Philippe Robin, Lauriane Fritsch, Robert Young, Nadya Morozova, Romain Fenouil, Nicolas Descostes, Jean Christophe Andrau, Jacques Mathieu, Ali Hamiche, Slimane Ait-Si-Ali, Christian Muchardt, Eric Batsché, Annick Harel-Bellan

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Abstract

Argonaute proteins play a major part in transcriptional gene silencing in many organisms, but their role in the nucleus of somatic mammalian cells remains elusive. Here, we have immunopurified human Argonaute-1 and Argonaute-2 (AGO1 and AGO2) chromatin-embedded proteins and found them associated with chromatin modifiers and, notably, with splicing factors. Using the CD44 gene as a model, we show that AGO1 and AGO2 facilitate spliceosome recruitment and modulate RNA polymerase II elongation rate, thereby affecting alternative splicing. Proper AGO1 and AGO2 recruitment to CD44 transcribed regions required the endonuclease Dicer and the chromobox protein HP1γ, and resulted in increased histone H3 lysine 9 methylation on variant exons. Our data thus uncover a new model for the regulation of alternative splicing, in which Argonaute proteins couple RNA polymerase II elongation to chromatin modification.

Original languageEnglish
Pages (from-to)998-1005
Number of pages8
JournalNature Structural and Molecular Biology
Volume19
Issue number10
DOIs
Publication statusPublished - 1 Oct 2012

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ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

Cite this

Ameyar-Zazoua, M., Rachez, C., Souidi, M., Robin, P., Fritsch, L., Young, R., Morozova, N., Fenouil, R., Descostes, N., Andrau, J. C., Mathieu, J., Hamiche, A., Ait-Si-Ali, S., Muchardt, C., Batsché, E., & Harel-Bellan, A. (2012). Argonaute proteins couple chromatin silencing to alternative splicing. Nature Structural and Molecular Biology, 19(10), 998-1005. https://doi.org/10.1038/nsmb.2373