ICR Noncoding RNA Expression Controls Imprinting and DNA Replication at the Dlk1-Dio3 Domain

Kota, Satya K.; Llères, David; Bouschet, Tristan; Hirasawa, Ryutaro; Marchand, Alice; Begon-Pescia, Christina; Sanli, Ildem; Arnaud, Philippe; Journot, Laurent; Girardot, Michael; Feil, Robert

doi:10.1016/j.devcel.2014.08.009

Cited by 66 publications

(103 citation statements)

References 64 publications

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“…The open chromatin signature of the corresponding region on the maternal allele of the IG-DMR could enable an activating function of AFF3 through this enhancer for regulating expression of the Dlk1-Dio3 locus, which is transcribed as a single polycistron. Consistent with these findings, a recent study found that enhancer-like noncoding RNAs emanating from the Dlk1-Dio3 ICR were required for the expression of the maternally expressed genes in the cluster (Kota et al 2014).…”

Section: Meg3 Mirnas Rian Mirnas Mirg Mir882supporting

confidence: 67%

Regulation of the imprinted Dlk1-Dio3 locus by allele-specific enhancer activity

et al. 2016

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Genomic imprinting is a critical developmental process characteristic of parent of origin-specific gene expression. It is well accepted that differentially DNA-methylated regions (DMRs) and enhancers are two major classes of ciselements determining parent of origin-specific gene expression, with each recruiting different sets of transcription factors. Previously, we identified the AF4/FMR2 (AFF) family protein AFF3 within the transcription elongation complex SEC-L3. Here, we report that AFF3 can specifically bind both gametic DMRs (gDMRs) and enhancers within imprinted loci in an allele-specific manner. We identify the molecular regulators involved in the recruitment of AFF3 to gDMRs and provide mechanistic insight into the requirement of AFF3 at an enhancer for the expression of an ∼200-kb polycistronic transcript within the imprinted Dlk1-Dio3 locus. Our data suggest that the heterochromatic environment at the gDMR reinforces silencing of its related enhancer by controlling the binding and activity of AFF3 in an allele-specific manner. In summary, this study provides molecular details about the regulation of dosage-critical imprinted gene expression through the regulated binding of the transcription elongation factor AFF3 between a DMR and an enhancer.

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Section: Meg3 Mirnas Rian Mirnas Mirg Mir882supporting

confidence: 67%

Regulation of the imprinted Dlk1-Dio3 locus by allele-specific enhancer activity

et al. 2016

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“…In agreement with low levels of Dlk1 transcription in pluripotent cells (Kota et al, 2014), no reporter gene expression could be detected in naïve iPSCs. However, exposure to the differentiation-inducing agent retinoic acid (RA) yielded cells with readily detectable reporter gene fluorescence.…”

Section: Resultsmentioning

confidence: 54%

A reporter model to visualize imprinting stability at the Dlk1 locus during mouse development and in pluripotent cells

Swanzey

Stadtfeld

2016

Development

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Genomic imprinting results in the monoallelic expression of genes that encode important regulators of growth and proliferation. Dysregulation of imprinted genes, such as those within the Dlk1-Dio3 locus, is associated with developmental syndromes and specific diseases. Our ability to interrogate causes of imprinting instability has been hindered by the absence of suitable model systems. Here, we describe a Dlk1 knock-in reporter mouse that enables single-cell visualization of allele-specific expression and prospective isolation of cells, simultaneously. We show that this ‘imprinting reporter mouse’ can be used to detect tissue-specific Dlk1 expression patterns in developing embryos. We also apply this system to pluripotent cell culture and demonstrate that it faithfully indicates DNA methylation changes induced upon cellular reprogramming. Finally, the reporter system reveals the role of elevated oxygen levels in eroding imprinted Dlk1 expression during prolonged culture and in vitro differentiation. The possibility to study allele-specific expression in different contexts makes our reporter system a useful tool to dissect the regulation of genomic imprinting in normal development and disease.

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“…In some contexts, nuclear lamina association has previously been shown to lead to reduction in gene expression (Finlan et al 2008). It has recently been shown that in ES cells, the maternally inherited Dlk1-Dio3 chromosome, which is highly expressed for Meg3 (Gtl2), is preferentially located internally in the nucleus, and the paternally inherited locus from which little expression is observed is located peripherally (Kota et al 2014). Perturbation of maternal gene expression by knocking down expression from the IG-DMR resulted in more peripheral localization, indicating that lack of expression itself may target a region to the periphery (Kota et al 2014).…”

Section: Gain Of Function In Gene Regulation and Chromosome Architecturementioning

confidence: 99%

“…It has recently been shown that in ES cells, the maternally inherited Dlk1-Dio3 chromosome, which is highly expressed for Meg3 (Gtl2), is preferentially located internally in the nucleus, and the paternally inherited locus from which little expression is observed is located peripherally (Kota et al 2014). Perturbation of maternal gene expression by knocking down expression from the IG-DMR resulted in more peripheral localization, indicating that lack of expression itself may target a region to the periphery (Kota et al 2014). Here, we show that upon maternal transmission of del L1rep , no significant changes in Meg3 (Gtl2) expression or any other genes in the domain was observed in any tissues analyzed.…”

Section: Gain Of Function In Gene Regulation and Chromosome Architecturementioning

confidence: 99%

Targeted deletion of a 170-kb cluster of LINE-1 repeats and implications for regional control

et al. 2018

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Approximately half the mammalian genome is composed of repetitive sequences, and accumulating evidence suggests that some may have an impact on genome function. Here, we characterized a large array class of repeats of long-interspersed elements (LINE-1). Although widely distributed in mammals, locations of such arrays are species specific. Using targeted deletion, we asked whether a 170-kb LINE-1 array located at a mouse imprinted domain might function as a modulator of local transcriptional control. The LINE-1 array is lamina associated in differentiated ES cells consistent with its AT-richness, and although imprinting occurs both proximally and distally to the array, active LINE-1 transcripts within the tract are biallelically expressed. Upon deletion of the array, no perturbation of imprinting was observed, and abnormal phenotypes were not detected in maternal or paternal heterozygous or homozygous mutant mice. The array does not shield nonimprinted genes in the vicinity from local imprinting control. Reduced neural expression of protein-coding genes observed upon paternal transmission of the deletion is likely due to the removal of a brain-specific enhancer embedded within the LINE array. Our findings suggest that presence of a 170-kb LINE-1 array reflects the tolerance of the site for repeat insertion rather than an important genomic function in normal development.

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ICR Noncoding RNA Expression Controls Imprinting and DNA Replication at the Dlk1-Dio3 Domain

Cited by 66 publications

References 64 publications

Regulation of the imprinted Dlk1-Dio3 locus by allele-specific enhancer activity

Regulation of the imprinted Dlk1-Dio3 locus by allele-specific enhancer activity

A reporter model to visualize imprinting stability at the Dlk1 locus during mouse development and in pluripotent cells

Targeted deletion of a 170-kb cluster of LINE-1 repeats and implications for regional control

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