Argonaute-1 directs siRNA-mediated transcriptional gene silencing in human cells.
Argonaute proteins are the core components of effector complexes that facilitate RNA interference (RNAi). Small interfering RNAs (siRNAs) targeted to promoter regions mediate transcriptional gene silencing (TGS) in human cells through heterochromatin formation. RNAi effector complexes have yet to be implicated in the mechanism of mammalian TGS. Here we describe the role of the human Argonaute-1 homolog (AGO1) in directing TGS at the promoters for human immunodeficiency virus-1 coreceptor CCR5 and tumor suppressor RASSF1A. AGO1 associates with RNA polymerase II (RNAPII) and is required for histone H3 Lys9 dimethylation and TGS. AGO1, TAR RNA-binding protein-2 (7TRBP2) and Polycomb protein EZH2 colocalize to the siRNA-targeted RASSF1A promoter, implicating Polycomb silencing in the mechanism of mammalian TGS. These results establish a connection between RNAi components AGO1 and TRBP2, RNAPII transcription and Polycomb-regulated control of gene expression.
Kim
Daniel H
DH
Graduate School of Biological Sciences, Beckman Research Institute of the City of Hope, 1450 E. Duarte Road, Duarte, California 91010, USA.
Villeneuve
Louisa M
LM
Morris
Kevin V
KV
Rossi
John J
JJ
D060565:Argonaute Proteins; D002478:Cells, Cultured; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000378:metabolism; D000071221:Enhancer of Zeste Homolog 2 Protein; D039642:Eukaryotic Initiation Factors / Q000378:metabolism*; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D010766:Phosphorylation; D063151:Polycomb Repressive Complex 2; D063146:Polycomb-Group Proteins; D011401:Promoter Regions, Genetic / Q000235:genetics; D034622:RNA Interference; D012319:RNA Polymerase II / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism; D019713:Receptors, CCR5 / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D000099253:Trans-Activation Responsive RNA-Binding Protein
D060565:Argonaute Proteins; D004268:DNA-Binding Proteins; D000071221:Enhancer of Zeste Homolog 2 Protein; D039642:Eukaryotic Initiation Factors; D006657:Histones; D063151:Polycomb Repressive Complex 2; D063146:Polycomb-Group Proteins; D012319:RNA Polymerase II; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D019713:Receptors, CCR5; D012097:Repressor Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000099253:Trans-Activation Responsive RNA-Binding Protein; C115848:AGO1 protein, human; C411762:RASSF1 protein, human; C498409:EZH2 protein, human