Uncoupling antisense-mediated silencing and DNA methylation in the imprinted Gnas cluster.

Christine Williamson, Simon Ball, Claire Dawson, Stuti Mehta, Colin Beechey, Martin Fray, Lydia Teboul, Terence Dear, Gavin Kelsey, Jo Peters

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    68 Citations (Scopus)

    Abstract

    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.

    Original languageEnglish
    Article numbere1001347
    Pages (from-to)Art e1001347
    Number of pages15
    JournalPloS Genetics
    Volume7
    Issue number3
    DOIs
    Publication statusPublished - Mar 2011

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    Williamson, C., Ball, S., Dawson, C., Mehta, S., Beechey, C., Fray, M., Teboul, L., Dear, T., Kelsey, G., & Peters, J. (2011). Uncoupling antisense-mediated silencing and DNA methylation in the imprinted Gnas cluster. PloS Genetics, 7(3), Art e1001347. [e1001347]. https://doi.org/10.1371/journal.pgen.1001347