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...
Main Authors: | , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Public Library of Science (PLoS)
2011-03-01
|
Series: | PLoS Genetics |
Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21455290/pdf/?tool=EBI |
id |
doaj-b4389291b05d4aa4982c4e464c144d09 |
---|---|
record_format |
Article |
spelling |
doaj-b4389291b05d4aa4982c4e464c144d092021-04-21T14:30:56ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042011-03-0173e100134710.1371/journal.pgen.1001347Uncoupling antisense-mediated silencing and DNA methylation in the imprinted Gnas cluster.Christine M WilliamsonSimon T BallClaire DawsonStuti MehtaColin V BeecheyMartin FrayLydia TeboulT Neil DearGavin KelseyJo PetersThere 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.https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21455290/pdf/?tool=EBI |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
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 |
spellingShingle |
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. PLoS Genetics |
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) |
series |
PLoS Genetics |
issn |
1553-7390 1553-7404 |
publishDate |
2011-03-01 |
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. |
url |
https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21455290/pdf/?tool=EBI |
work_keys_str_mv |
AT christinemwilliamson uncouplingantisensemediatedsilencinganddnamethylationintheimprintedgnascluster AT simontball uncouplingantisensemediatedsilencinganddnamethylationintheimprintedgnascluster AT clairedawson uncouplingantisensemediatedsilencinganddnamethylationintheimprintedgnascluster AT stutimehta uncouplingantisensemediatedsilencinganddnamethylationintheimprintedgnascluster AT colinvbeechey uncouplingantisensemediatedsilencinganddnamethylationintheimprintedgnascluster AT martinfray uncouplingantisensemediatedsilencinganddnamethylationintheimprintedgnascluster AT lydiateboul uncouplingantisensemediatedsilencinganddnamethylationintheimprintedgnascluster AT tneildear uncouplingantisensemediatedsilencinganddnamethylationintheimprintedgnascluster AT gavinkelsey uncouplingantisensemediatedsilencinganddnamethylationintheimprintedgnascluster AT jopeters uncouplingantisensemediatedsilencinganddnamethylationintheimprintedgnascluster |
_version_ |
1714668313504645120 |