Transcriptional silencing of long noncoding RNA GNG12-AS1 uncouples its transcriptional and product-related functions

Lovorka Stojic (), Malwina Niemczyk, Arturo Orjalo, Yoko Ito, Anna Elisabeth Maria Ruijter, Santiago Uribe-Lewis, Nimesh Joseph, Stephen Weston, Suraj Menon, Duncan T. Odom, John Rinn, Fanni Gergely and Adele Murrell ()
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Lovorka Stojic: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way
Malwina Niemczyk: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way
Arturo Orjalo: Biosearch Technologies Inc.
Yoko Ito: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way
Anna Elisabeth Maria Ruijter: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way
Santiago Uribe-Lewis: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way
Nimesh Joseph: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way
Stephen Weston: Centre for Regenerative Medicine, University of Bath, Claverton Down
Suraj Menon: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way
Duncan T. Odom: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way
John Rinn: Harvard University
Fanni Gergely: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way
Adele Murrell: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: Abstract Long noncoding RNAs (lncRNAs) regulate gene expression via their RNA product or through transcriptional interference, yet a strategy to differentiate these two processes is lacking. To address this, we used multiple small interfering RNAs (siRNAs) to silence GNG12-AS1, a nuclear lncRNA transcribed in an antisense orientation to the tumour-suppressor DIRAS3. Here we show that while most siRNAs silence GNG12-AS1 post-transcriptionally, siRNA complementary to exon 1 of GNG12-AS1 suppresses its transcription by recruiting Argonaute 2 and inhibiting RNA polymerase II binding. Transcriptional, but not post-transcriptional, silencing of GNG12-AS1 causes concomitant upregulation of DIRAS3, indicating a function in transcriptional interference. This change in DIRAS3 expression is sufficient to impair cell cycle progression. In addition, the reduction in GNG12-AS1 transcripts alters MET signalling and cell migration, but these are independent of DIRAS3. Thus, differential siRNA targeting of a lncRNA allows dissection of the functions related to the process and products of its transcription.

Date: 2016
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DOI: 10.1038/ncomms10406

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