Enhancer-driven chromatin interactions during development promote escape from silencing by a long non-coding RNA

Korostowski, Lisa; Raval, Anjali; Breuer, Gillian; Engel, Nora

doi:10.1186/1756-8935-4-21

Cited by 31 publications

(34 citation statements)

References 22 publications

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“…Enrichment of enhancerspecific chromatin marks H3K27ac, together with H3K4me1 over the actively transcribed NIGs in our ChIP-on-chip data, suggests that these enhancer-specific chromatin marks may provide immunity against strong silencing effects of Kcnq1ot1 RNA. This is further supported by a recent observation that tissue-and developmental-specific escape of silencing of the Kcnq1 gene in neonatal heart tissue is mediated by a heart-specific enhancer (Korostowski et al, 2011). As H3K27me3 and H3K27ac are present in a mutually exclusive fashion (Pasini et al, 2010), high H3K27ac levels over the actively transcribed NIGs and over the active genes on the inactive X chromosome could prevent the nucleation of the repressive histone modifications.…”

Section: Research Articlesupporting

confidence: 58%

Long noncoding RNA-mediated maintenance of DNA methylation and transcriptional gene silencing

et al. 2012

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SUMMARYEstablishment of silencing by noncoding RNAs (ncRNAs) via targeting of chromatin remodelers is relatively well investigated; however, their role in the maintenance of silencing is poorly understood. Here, we explored the functional role of the long ncRNA Kcnq1ot1 in the maintenance of transcriptional gene silencing in the one mega-base Kcnq1 imprinted domain in a transgenic mouse model. By conditionally deleting the Kcnq1ot1 ncRNA at different stages of mouse development, we suggest that Kcnq1ot1 ncRNA is required for the maintenance of the silencing of ubiquitously imprinted genes (UIGs) at all developmental stages. In addition, Kcnq1ot1 ncRNA is also involved in guiding and maintaining the CpG methylation at somatic differentially methylated regions flanking the UIGs, which is a hitherto unknown role for a long ncRNA. On the other hand, silencing of some of the placental-specific imprinted genes (PIGs) is maintained independently of Kcnq1ot1 ncRNA. Interestingly, the non-imprinted genes (NIGs) that escape RNA-mediated silencing are enriched with enhancer-specific modifications. Taken together, this study illustrates the gene-specific maintenance mechanisms operational at the Kcnq1 locus for tissue-specific transcriptional gene silencing and activation.

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Section: Research Articlesupporting

confidence: 58%

Long noncoding RNA-mediated maintenance of DNA methylation and transcriptional gene silencing

et al. 2012

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“…Kcnq1 , one such exception, is expressed from the maternal allele during early embryogenesis and transitions to biallelic expression during fetal heart development. This transition coincides with conformational changes involving the interaction between the Kcnq1 promoter and heart-specific enhancers [18]. Based on our previous studies, we hypothesized that paternal expression of Kcnq1ot1 represses Kcnq1 in cis , but this effect is countered when enhancer-driven activity of Kcnq1 becomes established during heart development.…”

Section: Introductionmentioning

confidence: 74%

The Kcnq1ot1 Long Non-Coding RNA Affects Chromatin Conformation and Expression of Kcnq1, but Does Not Regulate Its Imprinting in the Developing Heart

Korostowski¹,

Sedlak²,

2012

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Although many of the questions raised by the discovery of imprinting have been answered, we have not yet accounted for tissue- or stage-specific imprinting. The Kcnq1 imprinted domain exhibits complex tissue-specific expression patterns co-existing with a domain-wide cis-acting control element. Transcription of the paternally expressed antisense non-coding RNA Kcnq1ot1 silences some neighboring genes in the embryo, while others are unaffected. Kcnq1 is imprinted in early cardiac development but becomes biallelic after midgestation. To explore this phenomenon and the role of Kcnq1ot1, we used allele-specific assays and chromosome conformational studies in wild-type mice and mice with a premature termination mutation for Kcnq1ot1. We show that Kcnq1 imprinting in early heart is established and maintained independently of Kcnq1ot1 expression, thus excluding a role for Kcnq1ot1 in repressing Kcnq1, even while silencing other genes in the domain. The exact timing of the mono- to biallelic transition is strain-dependent, with the CAST/EiJ allele becoming activated earlier and acquiring higher levels than the C57BL/6J allele. Unexpectedly, Kcnq1ot1 itself also switches to biallelic expression specifically in the heart, suggesting that tissue-specific loss of imprinting may be common during embryogenesis. The maternal Kcnq1ot1 transcript is shorter than the paternal ncRNA, and its activation depends on an alternative transcriptional start site that bypasses the maternally methylated promoter. Production of Kcnq1ot1 on the maternal chromosome does not silence Cdkn1c. We find that in later developmental stages, however, Kcnq1ot1 has a role in modulating Kcnq1 levels, since its absence leads to overexpression of Kcnq1, an event accompanied by an aberrant three-dimensional structure of the chromatin. Thus, our studies reveal regulatory mechanisms within the Kcnq1 imprinted domain that operate exclusively in the heart on Kcnq1, a gene crucial for heart development and function. We also uncover a novel mechanism by which an antisense non-coding RNA affects transcription through regulating chromatin flexibility and access to enhancers.

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“…S6). This could indicate that insertion of the truncation cassette disrupted a currently undefined negative regulatory element for these two genes; in this regard, it is notable that recent evidence supports the existence of multiple enhancer elements in the KvDMR1/Kcnq1ot1 region (Korostowski et al, 2011;Schultz et al, 2015). Disruption of a gene repressor/silencer at this insertion site may also explain the apparently less efficient silencing effect that insertion of the YJ11 cassette has on Cdkn1c and Kcnq1 (Figs S5 and S6).…”

Section: Discussionmentioning

confidence: 92%

Blocked transcription through KvDMR1 results in absence of methylation and gene silencing resembling Beckwith-Wiedemann syndrome

et al. 2017

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The maternally methylated KvDMR1 ICR regulates imprinted expression of a cluster of maternally expressed genes on human chromosome 11p15.5. Disruption of imprinting leads to BeckwithWiedemann syndrome (BWS), an overgrowth and cancer predisposition condition. In the majority of individuals with BWS, maternal-specific methylation at KvDMR1 is absent and genes under its control are repressed. We analyzed a mouse model carrying a poly(A) truncation cassette inserted to prevent RNA transcripts from elongation through KvDMR1. Maternal inheritance of this mutation resulted in absence of DNA methylation at KvDMR1, which led to biallelic expression of Kcnq1ot1 and suppression of maternally expressed genes. This study provides further evidence that transcription is required for establishment of methylation at maternal gametic DMRs. More importantly, this mouse model recapitulates the molecular phenotypic characteristics of the most common form of BWS, including loss of methylation at KvDMR1 and biallelic repression of Cdkn1c, suggesting that deficiency of maternal transcription through KvDMR1 may be an underlying cause of some BWS cases.

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Enhancer-driven chromatin interactions during development promote escape from silencing by a long non-coding RNA

Cited by 31 publications

References 22 publications

Long noncoding RNA-mediated maintenance of DNA methylation and transcriptional gene silencing

Long noncoding RNA-mediated maintenance of DNA methylation and transcriptional gene silencing

The Kcnq1ot1 Long Non-Coding RNA Affects Chromatin Conformation and Expression of Kcnq1, but Does Not Regulate Its Imprinting in the Developing Heart

Blocked transcription through KvDMR1 results in absence of methylation and gene silencing resembling Beckwith-Wiedemann syndrome

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