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Non-Coding RNA 2015, 1(3), 246-265; doi:10.3390/ncrna1030246

Antisense Activity across the Nesp Promoter is Required for Nespas-Mediated Silencing in the Imprinted Gnas Cluster

1
MRC Harwell, Mammalian Genetics Unit, Harwell Campus, Oxfordshire OX110RD, UK
2
Epigenetics Programme, The Babraham Institute, Cambridge CB223AT, UK
3
Mary Lyon Centre, MRC Harwell, Harwell Campus, Oxfordshire OX110RD, UK
4
Centre for Trophoblast Research, University of Cambridge, Cambridge CB23EG, UK
5
Current address: MRC Functional Genomics Unit, Department of Physiology Anatomy & Genetics, Le Gros Clark Building, University of Oxford, South Parks Road, Oxford OX13QX, UK
6
Current Address: MRC Harwell, Harwell Campus, Oxfordshire OX110RD, UK
7
Current address: GI Division, Their 340, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
8
Current address: Mary Lyon Centre, MRC Harwell, Harwell Campus, Oxfordshire OX110RD, UK
9
Current address: Genome Function Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital Campus, London W120NN, UK
10
Current address: West London Free School, 2 Bridge Avenue, Hammersmith, London W69JP, UK
11
Current address: Molecular, Structural and Computational Biology Division, Victor Chang Cardiac Research Institute, Darlinghurst, NSW 2010, Australia
*
Author to whom correspondence should be addressed.
Academic Editor: George A. Calin
Received: 8 October 2015 / Revised: 17 November 2015 / Accepted: 17 November 2015 / Published: 30 November 2015
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Abstract

Macro long non-coding RNAs (lncRNAs) play major roles in gene silencing in inprinted gene clusters. Within the imprinted Gnas cluster, the paternally expressed Nespas lncRNA downregulates its sense counterpart Nesp. To explore the mechanism of action of Nespas, we generated two new knock-in alleles to truncate Nespas upstream and downstream of the Nesp promoter. We show that Nespas is essential for methylation of the Nesp differentially methylated region (DMR), but higher levels of Nespas are required for methylation than are needed for downregulation of Nesp. Although Nespas is transcribed for over 27 kb, only Nespas transcript/transcription across a 2.6 kb region that includes the Nesp promoter is necessary for methylation of the Nesp DMR. In both mutants, the levels of Nespas were extraordinarily high, due at least in part to increased stability, an effect not seen with other imprinted lncRNAs. However, even when levels were greatly raised, Nespas remained exclusively cis-acting. We propose Nespas regulates Nesp methylation and expression to ensure appropriate levels of expression of the protein coding transcripts Gnasxl and Gnas on the paternal chromosome. Thus, Nespas mediates paternal gene expression over the entire Gnas cluster via a single gene, Nesp. View Full-Text
Keywords: long non-coding RNA; antisense; genomic imprinting; epigenetic silencing; Nespas; Nesp; Gnas cluster long non-coding RNA; antisense; genomic imprinting; epigenetic silencing; Nespas; Nesp; Gnas cluster
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Tibbit, C.J.; Williamson, C.M.; Mehta, S.; Ball, S.T.; Chotalia, M.; Nottingham, W.T.; Eaton, S.A.; Quwailid, M.M.; Teboul, L.; Kelsey, G.; Peters, J. Antisense Activity across the Nesp Promoter is Required for Nespas-Mediated Silencing in the Imprinted Gnas Cluster. Non-Coding RNA 2015, 1, 246-265.

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