title: Argonaute proteins couple chromatin silencing to alternative splicing.
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.
authors.affiliation: Université Paris Sud, Laboratoire Epigenetique et Cancer, Formation de Recherche en Evolution, Gif-Sur-Yvette, France.
authors.forename: Maya
authors.initials: M
authors.lastname: Ameyar-Zazoua
authors.forename: Christophe
authors.initials: C
authors.lastname: Rachez
authors.forename: Mouloud
authors.initials: M
authors.lastname: Souidi
authors.forename: Philippe
authors.initials: P
authors.lastname: Robin
authors.forename: Lauriane
authors.initials: L
authors.lastname: Fritsch
authors.forename: Robert
authors.initials: R
authors.lastname: Young
authors.forename: Nadya
authors.initials: N
authors.lastname: Morozova
authors.forename: Romain
authors.initials: R
authors.lastname: Fenouil
authors.forename: Nicolas
authors.initials: N
authors.lastname: Descostes
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Andrau
authors.forename: Jacques
authors.initials: J
authors.lastname: Mathieu
authors.forename: Ali
authors.initials: A
authors.lastname: Hamiche
authors.forename: Slimane
authors.initials: S
authors.lastname: Ait-Si-Ali
authors.forename: Christian
authors.initials: C
authors.lastname: Muchardt
authors.forename: Eric
authors.initials: E
authors.lastname: Batsché
authors.forename: Annick
authors.initials: A
authors.lastname: Harel-Bellan
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D060565:Argonaute Proteins / Q000235:genetics / Q000378:metabolism*; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism; D039642:Eukaryotic Initiation Factors / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000502:physiology; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D051379:Mice; D012322:RNA Precursors / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering; D043244:Ribonuclease III / Q000235:genetics / Q000378:metabolism; D017381:Spliceosomes / Q000378:metabolism
chemical_list: C115848:AGO1 protein, human; C466422:AGO2 protein, human; C526735:Ago2 protein, mouse; D060565:Argonaute Proteins; C518294:CBX3 protein, human; C497483:CD44 protein, human; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D039642:Eukaryotic Initiation Factors; D006657:Histones; D018960:Hyaluronan Receptors; D012322:RNA Precursors; D034741:RNA, Small Interfering; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases; D008239:Lysine