PRC2 is dispensable forHOTAIR-mediated transcriptional repression.
Long non-coding RNAs (lncRNAs) play diverse roles in physiological and pathological processes. Several lncRNAs have been suggested to modulate gene expression by guiding chromatin-modifying complexes to specific sites in the genome. However, besides the example of Xist, clear-cut evidence demonstrating this novel mode of regulation remains sparse. Here, we focus onHOTAIR, a lncRNA that is overexpressed in several tumor types and previously proposed to play a key role in gene silencing through direct recruitment of Polycomb Repressive Complex 2 (PRC2) to defined genomic loci. Using genetic tools and a novel RNA-tethering system, we investigated the interplay betweenHOTAIRand PRC2 in gene silencing. Surprisingly, we observed that forced overexpression ofHOTAIRin breast cancer cells leads to subtle transcriptomic changes that appear to be independent of PRC2. Mechanistically, we found that artificial tethering ofHOTAIRto chromatin causes transcriptional repression, but that this effect does not require PRC2. Instead, PRC2 recruitment appears to be a consequence of gene silencing. We propose that PRC2 binding to RNA might serve functions other than chromatin targeting.
Institut Curie, PSL Research University, Paris, France.|INSERM U934, CNRS UMR3215, Paris, France.
Manuela
M
Portoso
Institut Curie, PSL Research University, Paris, France.|INSERM U934, CNRS UMR3215, Paris, France.
Roberta
R
Ragazzini
Institut Curie, PSL Research University, Paris, France.|INSERM U934, CNRS UMR3215, Paris, France.
Živa
Ž
Brenčič
Institut Curie, PSL Research University, Paris, France.|INSERM U934, CNRS UMR3215, Paris, France.
Arianna
A
Moiani
Institut Curie, PSL Research University, Paris, France.|INSERM U934, CNRS UMR3215, Paris, France.
Audrey
A
Michaud
Institut Curie, PSL Research University, Paris, France.|INSERM U934, CNRS UMR3215, Paris, France.
Ivaylo
I
Vassilev
Institut Curie, PSL Research University, Paris, France.|INSERM U934, CNRS UMR3215, Paris, France.
Michel
M
Wassef
Institut Curie, PSL Research University, Paris, France.|INSERM U900, Mines ParisTech, Paris, France.
Nicolas
N
Servant
CNRS UMR 8015, Université Paris Descartes, Paris, France.
Bruno
B
Sargueil
Institut Curie, PSL Research University, Paris, France raphael.margueron@curie.fr.|INSERM U934, CNRS UMR3215, Paris, France.
Raphaël
0000-0002-9093-7977
R
Margueron
D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism*; D062085:RNA, Long Noncoding / Q000096:biosynthesis* / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis* / Q000235:genetics; D014158:Transcription, Genetic
C561566:HOTAIR long untranslated RNA, human; D009363:Neoplasm Proteins; D062085:RNA, Long Noncoding; D012334:RNA, Neoplasm; D063151:Polycomb Repressive Complex 2
Polycomb; chromatin; lincRNA; transcription