Argonaute proteins couple chromatin silencing to alternative splicing

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.; Batsche, E.; Harel-Bellan, A.

Nat Struct Mol Biol

2012-10 / vol 19 / pages 998-1004


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 HP1gamma, 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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1545-9985 (Electronic) 1545-9985 (Linking)


Humans; Animals; Mice; Histones/metabolism; Methylation; Chromatin/genetics/*metabolism; Lysine/metabolism; HeLa Cells; *Alternative Splicing; Antigens, CD44/genetics/metabolism; Argonaute Proteins/genetics/*metabolism; Chromosomal Proteins, Non-Histone/genetics/metabolism; DEAD-box RNA Helicases/genetics/metabolism; Eukaryotic Initiation Factors/genetics/*metabolism; Fibroblasts/physiology; Ribonuclease III/genetics/metabolism; RNA Precursors/genetics/metabolism; RNA, Small Interfering; Spliceosomes/metabolism

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