The callipyge mutation enhances bidirectional long-range
            <i>DLK1-GTL2</i>
            intergenic transcription in cis

Takeda, Hitoshi; Caiment, Florian; Smit, Maria A.; Hiard, Samuel; Tordoir, Xavier; Cockett, Noelle E.; Georges, Michel; Charlier, Carole

doi:10.1073/pnas.0602844103

Cited by 48 publications

(39 citation statements)

References 27 publications

(34 reference statements)

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“…This element is located 9136 bp upstream from a conserved dodecamer motif that contains a single nucleotide polymorphism causing the Callipyge phenotype in sheep (29,33). Interestingly, the Callipyge mutation was recently shown to enhance bidirectional long range Dlk1-Gtl2 intergenic transcription in cis (25). Therefore, because the novel MAR4 activity appears to be stronger when the MAR4 is inserted in the antisense direction (with respect to the endogenous locus) in a reporter construct, its action may potentially favor transcription of antisense transcripts.…”

Section: Discussionmentioning

confidence: 99%

Genomic Matrix Attachment Region and Chromosome Conformation Capture Quantitative Real Time PCR Assays Identify Novel Putative Regulatory Elements at the Imprinted Dlk1/Gtl2 Locus

Braem

Recolin

Rancourt

et al. 2008

Journal of Biological Chemistry

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We previously showed that genomic imprinting regulates matrix attachment region activities at the mouse Igf2 (insulinlike growth factor 2) locus and that these activities are functionally linked to neighboring differentially methylated regions (DMRs). Here, we investigate the similarly structured Dlk1/Gtl2 imprinted domain and show that in the mouse liver, the G/Crich intergenic germ line-derived DMR, a sequence involved in domain-wide imprinting, is highly retained within the nuclear matrix fraction exclusively on the methylated paternal copy, reflecting its differential function on that chromosome. Therefore, not only "classical" A/T-rich matrix attachment region (MAR) sequences but also other important regulatory DNA elements (such as DMRs) can be recovered from genomic MAR assays following a high salt treatment. Interestingly, the recovery of one A/T-rich sequence (MAR4) from the "nuclear matrix" fraction is strongly correlated with gene expression. We show that this element possesses an intrinsic activity that favors transcription, and using chromosome conformation capture quantitative real time PCR assays, we demonstrate that the MAR4 interacts with the intergenic germ line-derived DMR specifically on the paternal allele but not with the Dlk1/Gtl2 promoters. Altogether, our findings shed a new light on gene regulation at this locus.Genomic imprinting is a parent-of-origin gene-silencing mechanism required for normal mammalian development. It involves germ line-specific epigenetic modifications acquired on restricted regions of the genome (imprinting control region or element) that control the imprinting of several genes often over several hundred kilobase pairs. Accumulating evidence indicates that monoallelic expression at mammalian imprinted loci largely results from allele-specific higher order chromatin structures that impair or favor gene expression. In this context, it becomes crucial to elucidate the genomic architecture associated with imprinted genes as well as to identify DNA sequences and factors involved in such higher order chromatin organization. In the present work, we examine the potential role of the so-called matrix attachment regions (MARs) 3 in imprinting and gene regulation. MARs have been operationally defined in "in vitro MAR assays" by their ability to "attach" to a purified nuclear matrix or scaffold. In that context, they appear as A/T-rich DNA sequences that may be involved in chromatin structure and gene expression (1). They are frequently associated with enhancers and promote chromatin accessibility and histone acetylation. Using a "genomic MAR" assay based on high salt treatment of purified nucleus preparations (2, 3), we previously showed that parental genomic imprinting controls MAR activities at the mouse Igf2 (insulin-like growth factor 2) locus. That work indicated that tissue-specific MARs and differentially methylated regions (DMRs) may act as bipartite elements controlling the long range activity of other regulatory elements such as enhancers (3), thus contributing t...

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Section: Discussionmentioning

confidence: 99%

Genomic Matrix Attachment Region and Chromosome Conformation Capture Quantitative Real Time PCR Assays Identify Novel Putative Regulatory Elements at the Imprinted Dlk1/Gtl2 Locus

Braem

Recolin

Rancourt

et al. 2008

Journal of Biological Chemistry

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“…Georgiades et al (40) found strong evidence for imprinting on chromosome 12, especially at the telomeric end of the chromosome where the genes involved in the callipyge mutation occur (33,38,39). However, Bwi12.1 maps proximal to the known imprinted region so it seems to represent a unique imprinting region, although imprinting has been implicated in the effects of a mutation (Adp) caused by a transgene insertion into the region of Bwi12.1 (40, 41).…”

Section: Discussionmentioning

confidence: 99%

Genomic imprinting effects on adult body composition in mice

Cheverud

Hager

Roseman³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Genomic imprinting results in the differential expression of genes, depending on which allele is inherited from the mother and which from the father. The effects of such differential gene expression are reflected in phenotypic differences between the reciprocal heterozygotes (Aa vs. aA). Although many imprinted genes have been identified and play a key role in development, little is known about the contribution of imprinting to quantitative variation in trait expression. Here, we examine this problem by mapping imprinting effects on adult body composition traits in the F 3 generation of an intercross between the Large (LG/J) and Small (SM/J) inbred mouse strains. We identified eight pleiotropic imprinted quantitative trait loci (iQTL) located throughout the genome. Most iQTL are in novel locations that have not previously been associated with imprinting effects, but those on chromosomes 7, 12, and centromeric 18 lie in regions previously identified as containing imprinted genes. Our results show that the effects of genomic imprinting are relatively small, with reciprocal heterozygotes differing by Ϸ0.25 standard deviation units and the effects at each locus accounting for 1% to 4% of the phenotypic variance. We detected a variety of imprinting patterns, with paternal expression being the most common. These results indicate that genomic imprinting has small, but detectable, effects on the normal variation of complex traits in adults and is likely to be more common than usually thought.epigenetics ͉ mouse ͉ obesity ͉ quantitative trait loci ͉ organs

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“…The characteristic molecular events of this genetic process include paternal overexpression of DLK1 and PEG11/RTL1 and normal maternal expression of Gtl2, Rian, antiPeg11, and miRs (19). The prevalent working model for polar overdominance predicts that maternal noncoding RNA within the Dlk1-Dio3 imprinting region may serve as a trans-regulator of DLK1 expression, thereby causing the CLPG phenotype (4).…”

Section: Discussionmentioning

confidence: 99%

“…Further analysis revealed a point mutation (A to G transition) within the intergenic region between the Dlk1 and Gtl2 genes of the imprinted Dlk1-Dio3 region (17,18), which affects a muscle-specific, long-range cis-acting control element (18). The point mutation in the paternal allele up-regulates the transcription of genes including Dlk1 and Peg11 in cis without altering the imprinting status (19). When this mutation occurs in the maternal allele, it up-regulates the expression of noncoding RNAs in the Dlk1-Dio3 region.…”

mentioning

confidence: 99%

Regulation of DLK1 by the maternally expressed miR-379/miR-544 cluster may underlie callipyge polar overdominance inheritance

Gao

Chen

Wang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Inheritance of the callipyge phenotype in sheep is an example of polar overdominance inheritance, an unusual mode of inheritance. To investigate the underlying molecular mechanism, we profiled the expression of the genes located in the Delta-like 1 homolog (Dlk1)-type III iodothyronine deiodinase (Dio3) imprinting region in mice. We found that the transcripts of the microRNA (miR) 379/miR-544 cluster were highly expressed in neonatal muscle and paralleled the expression of the Dlk1. We then determined the in vivo role of the miR-379/miR-544 cluster by establishing a mouse line in which the cluster was ablated. The maternal heterozygotes of young mutant mice displayed a hypertrophic tibialis anterior muscle, extensor digitorum longus muscle, gastrocnemius muscle, and gluteus maximus muscle and elevated expression of the DLK1 protein. Reduced expression of DLK1 was mediated by miR-329, a member of this cluster. Our results suggest that maternal expression of the imprinted miR-379/miR-544 cluster regulates paternal expression of the Dlk1 gene in mice. We therefore propose a miR-based molecular working model for polar overdominance inheritance. muscle hypertrophy | callipyge | DLK1 | miR-379/miR-544 cluster T he callipyge (CLPG) phenotype can be characterized by an increase in muscle mass due to muscular hypertrophy and a unique non-Mendelian mode of inheritance (1-3). CLPG individuals are born with normal muscle histology and develop muscle hypertrophy at ∼1 mo of age. This hypertrophy occurs primarily in the muscles of the pelvic limbs and loin and some muscles in the shoulder, which are enriched with a high proportion of type IIB fast-twitch glycolytic fibers (4). Although the molecular regulation of these hypertrophic processes is yet to be determined, Delta-like 1 homolog (DLK1) is found to be the causative protein (5-10). The unique mode of inheritance of the CLPG phenotype has attracted a great deal of attention within the scientific community. The CLPG offspring inherit the phenotype only when the mutated allele comes from the father and the wild-type allele from the mother (CLPG PAT /+ MAT ). CLPG PAT /CLPG MAT offspring exhibit a wild-type phenotype, despite carrying a CLPG mutation on the paternal chromosome. This unusual mode of inheritance led to the development of the genetic concept of polar overdominance (2, 11).The CLPG mutation has been mapped to the Dlk1-Dio3 imprinted domain, which spans ∼1 Mb and harbors at least three protein-encoding genes, including Dlk1, Peg11/Rtl1, and Dio3, and multiple noncoding RNA genes, including Gtl2, anti-Peg11/anti-Rtl1, Meg8, Mirg, C/D small nucleolar RNAs (snoRNAs), and microRNA clusters [the microRNA (miR) 379 and miR-127 clusters] (12-14). The coding genes are expressed paternally, whereas the noncoding genes are expressed maternally (15,16). Further analysis revealed a point mutation (A to G transition) within the intergenic region between the Dlk1 and Gtl2 genes of the imprinted Dlk1-Dio3 region (17, 18), which affects a muscle-specific, long-range cis-acting ...

show abstract

The callipyge mutation enhances bidirectional long-range DLK1-GTL2 intergenic transcription in cis

Cited by 48 publications

References 27 publications

Genomic Matrix Attachment Region and Chromosome Conformation Capture Quantitative Real Time PCR Assays Identify Novel Putative Regulatory Elements at the Imprinted Dlk1/Gtl2 Locus

Genomic Matrix Attachment Region and Chromosome Conformation Capture Quantitative Real Time PCR Assays Identify Novel Putative Regulatory Elements at the Imprinted Dlk1/Gtl2 Locus

Genomic imprinting effects on adult body composition in mice

Regulation of DLK1 by the maternally expressed miR-379/miR-544 cluster may underlie callipyge polar overdominance inheritance

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