Intronic RNAs mediate EZH2 regulation of epigenetic targets.
Epigenetic deregulation at a number of genomic loci is one of the hallmarks of cancer. A role for some RNA molecules in guiding repressive polycomb complex PRC2 to specific chromatin regions has been proposed. Here we use an in vivo cross-linking method to detect and identify direct PRC2-RNA interactions in human cancer cells, revealing a number of intronic RNA sequences capable of binding to the core component EZH2 and regulating the transcriptional output of its genomic counterpart. Overexpression of EZH2-bound intronic RNA for the H3K4 methyltransferase gene SMYD3 is concomitant with an increase in EZH2 occupancy throughout the corresponding genomic fragment and is sufficient to reduce levels of the endogenous transcript and protein, resulting in reduced growth capability in cell culture and animal models. These findings reveal the role of intronic RNAs in fine-tuning gene expression regulation at the level of transcriptional control.
Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, L'Hospitalet, Barcelona, Catalonia, Spain. sguil@idibell.cat
Sònia
S
Guil
Marta
M
Soler
Anna
A
Portela
Jordi
J
Carrère
Elena
E
Fonalleras
Antonio
A
Gómez
Alberto
A
Villanueva
Manel
M
Esteller
D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D007438:Introns; D051379:Mice; D008819:Mice, Nude; D063151:Polycomb Repressive Complex 2; D011485:Protein Binding; D012313:RNA / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*
D004268:DNA-Binding Proteins; D014157:Transcription Factors; D012313:RNA; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2