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Uncoupling Antisense-Mediated Silencing and DNA Methylation in the Imprinted Gnas Cluster

There is increasing evidence that non-coding macroRNAs are major elements for silencing imprinted genes, but their mechanism of action is poorly understood. Within the imprinted Gnas cluster on mouse chromosome 2, Nespas is a paternally expressed macroRNA that arises from an imprinting control regio...

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Detalles Bibliográficos
Autores principales: Williamson, Christine M., Ball, Simon T., Dawson, Claire, Mehta, Stuti, Beechey, Colin V., Fray, Martin, Teboul, Lydia, Dear, T. Neil, Kelsey, Gavin, Peters, Jo
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3063750/
https://www.ncbi.nlm.nih.gov/pubmed/21455290
http://dx.doi.org/10.1371/journal.pgen.1001347
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author Williamson, Christine M.
Ball, Simon T.
Dawson, Claire
Mehta, Stuti
Beechey, Colin V.
Fray, Martin
Teboul, Lydia
Dear, T. Neil
Kelsey, Gavin
Peters, Jo
author_facet Williamson, Christine M.
Ball, Simon T.
Dawson, Claire
Mehta, Stuti
Beechey, Colin V.
Fray, Martin
Teboul, Lydia
Dear, T. Neil
Kelsey, Gavin
Peters, Jo
author_sort Williamson, Christine M.
collection PubMed
description There is increasing evidence that non-coding macroRNAs are major elements for silencing imprinted genes, but their mechanism of action is poorly understood. Within the imprinted Gnas cluster on mouse chromosome 2, Nespas is a paternally expressed macroRNA that arises from an imprinting control region and runs antisense to Nesp, a paternally repressed protein coding transcript. Here we report a knock-in mouse allele that behaves as a Nespas hypomorph. The hypomorph mediates down-regulation of Nesp in cis through chromatin modification at the Nesp promoter but in the absence of somatic DNA methylation. Notably there is reduced demethylation of H3K4me3, sufficient for down-regulation of Nesp, but insufficient for DNA methylation; in addition, there is depletion of the H3K36me3 mark permissive for DNA methylation. We propose an order of events for the regulation of a somatic imprint on the wild-type allele whereby Nespas modulates demethylation of H3K4me3 resulting in repression of Nesp followed by DNA methylation. This study demonstrates that a non-coding antisense transcript or its transcription is associated with silencing an overlapping protein-coding gene by a mechanism independent of DNA methylation. These results have broad implications for understanding the hierarchy of events in epigenetic silencing by macroRNAs.
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spelling pubmed-30637502011-03-31 Uncoupling Antisense-Mediated Silencing and DNA Methylation in the Imprinted Gnas Cluster Williamson, Christine M. Ball, Simon T. Dawson, Claire Mehta, Stuti Beechey, Colin V. Fray, Martin Teboul, Lydia Dear, T. Neil Kelsey, Gavin Peters, Jo PLoS Genet Research Article There is increasing evidence that non-coding macroRNAs are major elements for silencing imprinted genes, but their mechanism of action is poorly understood. Within the imprinted Gnas cluster on mouse chromosome 2, Nespas is a paternally expressed macroRNA that arises from an imprinting control region and runs antisense to Nesp, a paternally repressed protein coding transcript. Here we report a knock-in mouse allele that behaves as a Nespas hypomorph. The hypomorph mediates down-regulation of Nesp in cis through chromatin modification at the Nesp promoter but in the absence of somatic DNA methylation. Notably there is reduced demethylation of H3K4me3, sufficient for down-regulation of Nesp, but insufficient for DNA methylation; in addition, there is depletion of the H3K36me3 mark permissive for DNA methylation. We propose an order of events for the regulation of a somatic imprint on the wild-type allele whereby Nespas modulates demethylation of H3K4me3 resulting in repression of Nesp followed by DNA methylation. This study demonstrates that a non-coding antisense transcript or its transcription is associated with silencing an overlapping protein-coding gene by a mechanism independent of DNA methylation. These results have broad implications for understanding the hierarchy of events in epigenetic silencing by macroRNAs. Public Library of Science 2011-03-24 /pmc/articles/PMC3063750/ /pubmed/21455290 http://dx.doi.org/10.1371/journal.pgen.1001347 Text en Williamson et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Williamson, Christine M.
Ball, Simon T.
Dawson, Claire
Mehta, Stuti
Beechey, Colin V.
Fray, Martin
Teboul, Lydia
Dear, T. Neil
Kelsey, Gavin
Peters, Jo
Uncoupling Antisense-Mediated Silencing and DNA Methylation in the Imprinted Gnas Cluster
title Uncoupling Antisense-Mediated Silencing and DNA Methylation in the Imprinted Gnas Cluster
title_full Uncoupling Antisense-Mediated Silencing and DNA Methylation in the Imprinted Gnas Cluster
title_fullStr Uncoupling Antisense-Mediated Silencing and DNA Methylation in the Imprinted Gnas Cluster
title_full_unstemmed Uncoupling Antisense-Mediated Silencing and DNA Methylation in the Imprinted Gnas Cluster
title_short Uncoupling Antisense-Mediated Silencing and DNA Methylation in the Imprinted Gnas Cluster
title_sort uncoupling antisense-mediated silencing and dna methylation in the imprinted gnas cluster
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3063750/
https://www.ncbi.nlm.nih.gov/pubmed/21455290
http://dx.doi.org/10.1371/journal.pgen.1001347
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