Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 19, Issue 10, Pages 998-U46Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.2373
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Funding
- European Commission Sixth Framework Programme (Integrated Project Silencing RNAs: Organisers and Coordinators of Complexity in Eukaryotic Organisms (SIROCCO) [LSHG-CT-2006-037900]
- Agence Nationale de la Recherche [ANR-11-BSV8-0013]
- Agence Nationale de la Recherche (ANR) [ANR-11-BSV8-0013] Funding Source: Agence Nationale de la Recherche (ANR)
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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 HP1 gamma, 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.
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