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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Autores principales:	Christine M Williamson, Simon T Ball, Claire Dawson, Stuti Mehta, Colin V Beechey, Martin Fray, Lydia Teboul, T Neil Dear, Gavin Kelsey, Jo Peters
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Genetics QH426-470
Acceso en línea:	https://doaj.org/article/b4389291b05d4aa4982c4e464c144d09
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spelling	oai:doaj.org-article:b4389291b05d4aa4982c4e464c144d092021-11-18T06:17:37ZUncoupling antisense-mediated silencing and DNA methylation in the imprinted Gnas cluster.1553-73901553-740410.1371/journal.pgen.1001347https://doaj.org/article/b4389291b05d4aa4982c4e464c144d092011-03-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21455290/pdf/?tool=EBIhttps://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404There 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.Christine M WilliamsonSimon T BallClaire DawsonStuti MehtaColin V BeecheyMartin FrayLydia TeboulT Neil DearGavin KelseyJo PetersPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 7, Iss 3, p e1001347 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Genetics QH426-470
spellingShingle	Genetics QH426-470 Christine M Williamson Simon T Ball Claire Dawson Stuti Mehta Colin V Beechey Martin Fray Lydia Teboul T Neil Dear Gavin Kelsey Jo Peters Uncoupling antisense-mediated silencing and DNA methylation in the imprinted Gnas cluster.
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.
format	article
author	Christine M Williamson Simon T Ball Claire Dawson Stuti Mehta Colin V Beechey Martin Fray Lydia Teboul T Neil Dear Gavin Kelsey Jo Peters
author_facet	Christine M Williamson Simon T Ball Claire Dawson Stuti Mehta Colin V Beechey Martin Fray Lydia Teboul T Neil Dear Gavin Kelsey Jo Peters
author_sort	Christine M Williamson
title	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_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_sort	uncoupling antisense-mediated silencing and dna methylation in the imprinted gnas cluster.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/b4389291b05d4aa4982c4e464c144d09
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Uncoupling antisense-mediated silencing and DNA methylation in the imprinted Gnas cluster.

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