PRC2 is dispensable for HOTAIR‐mediated transcriptional repression. (6th February 2017)

• Record Type: Journal Article
• Authors: Portoso, Manuela; Ragazzini, Roberta; Brenčič, Živa; Moiani, Arianna; Michaud, Audrey; Vassilev, Ivaylo; Wassef, Michel; Servant, Nicolas; Sargueil, Bruno; Margueron, Raphaël
• Is Part Of: EMBO journal. Volume 36:Number 8(2017)
• Page Start: 981
• Page End: 994
• Publication Date: 2017-02-06
• Subjects: chromatin -- lincRNA -- Polycomb -- transcription; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.201695335
• Languages: English
• ISSNs: 0261-4189

Abstract

Abstract: 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 on HOTAIR, 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 between HOTAIR and PRC2 in gene silencing. Surprisingly, we observed that forced overexpression of HOTAIR in breast cancer cells leads to subtle transcriptomic changes that appear to be independent of PRC2. Mechanistically, we found that artificial tethering of HOTAIR to 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. Synopsis: The ability of lncRNA HOTAIR to recruit chromatin‐modifying factors has served as a paradigm for lncRNA‐mediated repression of target genes. Contrary to expectation, HOTAIR can exert repressive effects independent of PRC2, whose recruitment may rather be a downstream consequence of gene silencing. Overexpression of lncRNA HOTAIR in breast cancer cells has limited transcriptional consequences. Artificial tethering of HOTAIR at a reporter transgene leads to transcriptional repression. The transcriptional repression mediated by HOTAIR is independent of PRC2. Abstract : Recruitment of chromatin‐modifying factors may not be the sought‐after mechanism for gene silencing by HOTAIR lncRNA, but rather its downstream consequence.