A developmental window of opportunity for imprinted gene silencing mediated by DNA methylation and the Kcnq1ot1 noncoding RNA

Green, Kelly; Lewis, Annabelle; Dawson, Claire; Dean, Wendy; Reinhart, Bonnie; Chaillet, J. Richard; Reik, Wolf

doi:10.1007/s00335-006-0092-9

Cited by 32 publications

(37 citation statements)

References 25 publications

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“…In previous studies of Dnmt1 c/c conceptuses, Kcnq1ot1 expression increased in embryos and became biallelic in embryos and placentas (15,27). In this study, we found that Kcnq1ot1 expression was significantly increased only in C7 ϫ B6…”

supporting

confidence: 52%

“…Furthermore, analysis of Dnmt1 mutant embryos has suggested that some genes may utilize different mechanisms to regulate imprinting in embryonic and extraembryonic tissues. In the Kcnq1 cluster, expression of genes that are imprinted only in the placenta, including Osbpl5, Tssc4, Cd81, and Ascl2, is unaffected in Dnmt1 c/c placentas (6,15,27,40). These genes are differentially marked by histone modifications in the placenta, with active histone modifications on the maternal, expressed allele and repressive marks on the silent paternal allele (27,43).…”

mentioning

confidence: 99%

“…These observations have led to the proposal that somatic DNMT1 is not required for maintenance of imprinting of these genes, which are instead regulated by histone modifications (27,43,46). However, placentas derived from Dnmt1 ⌬1o/⌬1o oocytes, which lack maternal DNMT1, do have biallelic expression of these genes, suggesting DNMT1 is required earlier to establish imprinting and is dispensable only later in development (15).…”

mentioning

confidence: 99%

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Domain-Specific Response of Imprinted Genes to Reduced DNMT1

Weaver

Sarkisian

Krapp

et al. 2010

Molecular and Cellular Biology

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Imprinted genes are expressed in a monoallelic, parent-of-origin-specific manner. Clusters of imprinted genes are regulated by imprinting control regions (ICRs) characterized by DNA methylation of one allele. This methylation is critical for imprinting; a reduction in the DNA methyltransferase DNMT1 causes a widespread loss of imprinting. To better understand the role of DNA methylation in the regulation of imprinting, we characterized the effects of Dnmt1 mutations on the expression of a panel of imprinted genes in the embryo and placenta. We found striking differences among imprinted domains. The Igf2 and Peg3 domains showed imprinting perturbations with both null and partial loss-of-function mutations, and both domains had pairs of coordinately regulated genes with opposite responses to loss of DNMT1 function, suggesting these domains employ similar regulatory mechanisms. Genes in the Kcnq1 domain were less sensitive to the absence of DNMT1. Cdkn1c exhibited imprinting perturbations only in null mutants, while Kcnq1 and Ascl2 were largely unaffected by a loss of DNMT1 function. These results emphasize the critical role for DNA methylation in imprinting and reveal the different ways it controls gene expression.

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supporting

confidence: 52%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Domain-Specific Response of Imprinted Genes to Reduced DNMT1

Weaver

Sarkisian

Krapp

et al. 2010

Molecular and Cellular Biology

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“…These include a causal role for ncRNAs in chromatin remodeling (Hirota et al, 2008) and gene silencing (Chaumeil et al, 2006;Green et al, 2007;Martianov et al, 2007). Our current findings provide a novel insight into the role of the Sat3 ncRNAs in the heat shock response.…”

Section: Discussionmentioning

confidence: 66%

Human satellite-III non-coding RNAs modulate heat-shock-induced transcriptional repression

Goenka

Sengupta

Pandey

et al. 2016

Journal of Cell Science

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The heat shock response is a conserved defense mechanism that protects cells from physiological stress, including thermal stress. Besides the activation of heat-shock-protein genes, the heat shock response is also known to bring about global suppression of transcription; however, the mechanism by which this occurs is poorly understood. One of the intriguing aspects of the heat shock response in human cells is the transcription of satellite-III (Sat3) long non-coding RNAs and their association with nuclear stress bodies (nSBs) of unknown function. Besides association with the Sat3 transcript, the nSBs are also known to recruit the transcription factors HSF1 and CREBBP, and several RNA-binding proteins, including the splicing factor SRSF1. We demonstrate here that the recruitment of CREBBP and SRSF1 to nSBs is Sat3-dependent, and that loss of Sat3 transcripts relieves the heat-shock-induced transcriptional repression of a few target genes. Conversely, forced expression of Sat3 transcripts results in the formation of nSBs and transcriptional repression even without a heat shock. Our results thus provide a novel insight into the regulatory role for the Sat3 transcripts in heatshock-dependent transcriptional repression.

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“…In parallel with X inactivation, the Kcnq1ot1 RNA is first paternally expressed in two-cell embryos, and inactivation of the cis linked genes is initiated in preimplantation and early postimplantation embryos (Lewis et al, 2006;Green et al, 2007). In placentae, the silenced domain extends over 780 kb, whereas in the embryo it is considerably smaller (400 kb; Fig.…”

Section: Introductionmentioning

confidence: 99%

The long noncoding RNA Kcnq1ot1 organises a lineage-specific nuclear domain for epigenetic gene silencing

et al. 2009

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Long noncoding RNAs are implicated in a number of regulatory functions in eukaryotic genomes. The paternally expressed long noncoding RNA (ncRNA)Kcnq1ot1 regulates epigenetic gene silencing in an imprinted gene cluster in cis over a distance of 400 kb in the mouse embryo, whereas the silenced region extends over 780 kb in the placenta. Gene silencing by the Kcnq1ot1 RNA involves repressive histone modifications, including H3K9me2 and H3K27me3,which are partly brought about by the G9a and Ezh2 histone methyltransferases. Here, we show that Kcnq1ot1 is transcribed by RNA polymerase II, is unspliced,is relatively stable and is localised in the nucleus. Analysis of conditional Dicer mutants reveals that the RNAi pathway is not involved in gene silencing in the Kcnq1ot1 cluster. Instead, using RNA/DNA FISH we show that the Kcnq1ot1 RNA establishes a nuclear domain within which the genes that are epigenetically inactivated in cis are frequently found, whereas nearby genes that are not regulated by Kcnq1ot1 are localised outside of the domain. The Kcnq1ot1 RNA domain is larger in the placenta than in the embryo, consistent with more genes in the cluster being silenced in the placenta. Our results show for the first time that autosomal long ncRNAs can establish nuclear domains, which might create a repressive environment for epigenetic silencing of adjacent genes. Long ncRNAs in imprinting clusters and the Xist RNA on the inactive X chromosome thus appear to regulate epigenetic gene silencing by similar mechanisms.

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A developmental window of opportunity for imprinted gene silencing mediated by DNA methylation and the Kcnq1ot1 noncoding RNA

Cited by 32 publications

References 25 publications

Domain-Specific Response of Imprinted Genes to Reduced DNMT1

Domain-Specific Response of Imprinted Genes to Reduced DNMT1

Human satellite-III non-coding RNAs modulate heat-shock-induced transcriptional repression

The long noncoding RNA Kcnq1ot1 organises a lineage-specific nuclear domain for epigenetic gene silencing

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