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Allele-specific enhancer interaction at the Peg3 imprinted domain.

ABSTRACT: The parental allele specificity of mammalian imprinted genes has been evolutionarily well conserved, although its functional constraints and associated mechanisms are not fully understood. In the current study, we generated a mouse mutant with switched active alleles driving the switch from paternal-to-maternal expression for Peg3 and the maternal-to-paternal expression for Zim1. The expression levels of Peg3 and Zim1, but not the spatial expression patterns, within the brain showed clear differences between wild type and mutant animals. We identified putative enhancers localized upstream of Peg3 that displayed allele-biased DNA methylation, and that also participate in allele-biased chromosomal conformations with regional promoters. Most importantly, these data suggest for the first time that long-distance enhancers may contribute to allelic expression within imprinted domains through allele-biased interactions with regional promoters.

SUBMITTER: Kim J

PROVIDER: S-EPMC6804975 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Allele and dosage specificity of the Peg3 imprinted domain.

Project description:The biological impetus for gene dosage and allele specificity of mammalian imprinted genes is not fully understood. To address this, we generated and analyzed four sets of mice from a single breeding scheme with varying allelic expression and gene dosage of the Peg3 domain. The mutants with abrogation of the two paternally expressed genes, Peg3 and Usp29, showed a significant decrease in growth rates for both males and females, while the mutants with biallelic expression of Peg3 and Usp29 resulted in an increased growth rate of female mice only. The mutant cohort with biallelic expression of Peg3 and Usp29 tended to have greater numbers of pups compared to the other genotypes. The mutants with switched active alleles displayed overall similar phenotypes to the wild type, but did show some differences in gene expression, suggesting potential non-redundant roles contributed by the maternal and paternal alleles. Overall, this study demonstrates a novel in vivo approach to investigate the allele and dosage specificity of mammalian imprinted domains.

| S-EPMC5937776 | biostudies-literature

YY1's role in the Peg3 imprinted domain.

Project description:The ICR (Imprinting Control Region) of the Peg3 (Paternally Expressed Gene 3) domain contains an unusual cluster of YY1 binding sites. In the current study, these YY1 binding sites were mutated to characterize the unknown roles in the mouse Peg3 domain. According to the results, paternal and maternal transmission of the mutant allele did not cause any major effect on the survival of the pups. In the mutants, the maternal-specific DNA methylation on the ICR was properly established and maintained, causing no major effect on the imprinting of the domain. In contrast, the paternal transmission resulted in changes in the expression levels of several genes: down-regulation of Peg3 and Usp29 and up-regulation of Zim1. These changes were more pronounced during the neonatal stage than during the adult stage. In the case of Peg3 and Zim1, the levels of the observed changes were also different between males and females, suggesting the different degrees of YY1 involvement between two sexes. Overall, the results indicated that YY1 is mainly involved in controlling the transcriptional levels, but not the DNA methylation, of the Peg3 domain.

| S-EPMC5526879 | biostudies-other

MacroH2A1 knockdown effects on the Peg3 imprinted domain.

Project description:BackgroundMacroH2A1 is a histone variant that is closely associated with the repressed regions of chromosomes. A recent study revealed that this histone variant is highly enriched in the inactive alleles of Imprinting Control Regions (ICRs).ResultsThe current study investigates the potential roles of macroH2A1 in genomic imprinting by lowering the cellular levels of the macroH2A1 protein. RNAi-based macroH2A1 knockdown experiments in Neuro2A cells changed the expression levels of a subset of genes, including Peg3 and Usp29 of the Peg3 domain. The expression of these genes was down-regulated, rather than up-regulated, in response to reduced protein levels of the potential repressor macroH2A1. This down-regulation was not accompanied with changes in the DNA methylation status of the Peg3 domain.ConclusionMacroH2A1 may not function as a transcriptional repressor for this domain, but that macroH2A1 may participate in the heterochromatin formation with functions yet to be discovered.

| S-EPMC2241636 | biostudies-literature

Parental and sexual conflicts over the Peg3 imprinted domain.

Project description:In the current study, the imprinting control region of the mouse Peg3 domain was deleted to test its functional impact on animal growth and survival. The paternal transmission of the deletion resulted in complete abolition of the transcription of two paternally expressed genes, Peg3 and Usp29, causing the reduced body weight of the pups. In contrast, the maternal transmission resulted in the unexpected transcriptional up-regulation of the remaining paternal allele of both Peg3 and Usp29, causing the increased body weight and survival rates. Thus, the imprinted maternal allele of the ICR may be a suppressor antagonistic to the active paternal allele of the ICR, suggesting a potential intralocus allelic conflict. The opposite outcomes between the two transmissions also justify the functional compromise that the maternal allele has become epigenetically repressed rather than genetically deleted during mammalian evolution. The mice homozygous for the deletion develop normally but with a skewed sex ratio, one male per litter, revealing its sex-biased effect. Overall, the Peg3 locus may have evolved to an imprinted domain to cope with both parental and sexual conflicts driven by its growth-stimulating paternal versus growth-suppressing maternal alleles.

| S-EPMC5128876 | biostudies-other

DNA methylation analysis of the mammalian PEG3 imprinted domain.

Project description:In this study, we performed the first systematic survey of DNA methylation status of the CpG islands of the PEG3 (Paternally expressed gene 3) imprinted domain in the mouse, cow, and human genomes. Previous studies have shown that the region surrounding the first exon of PEG3 contains a differentially methylated CpG island. In addition, we have discovered two previously unreported differentially methylated regions (DMR): one in the promoter region of mouse Zim3 and another in the promoter region of human USP29. In the cow, the Peg3-CpG island was the only area that showed DMR status. We have also examined the methylation status of several CpG islands in this region using human tumor-derived DNA. The CpG islands near PEG3 and USP29 both showed hypermethylation in DNA derived from breast and ovarian tumors. Overall, this study shows that the PEG3 imprinted domain of humans, cows, and mice contains differing numbers of DMRs, but the PEG3-CpG island is the only DMR that is conserved among these three species.

| S-EPMC2693452 | biostudies-literature

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

Project description: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 cis-elements 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.

| S-EPMC4701981 | biostudies-literature

Allele-specific aberration of imprinted domain chromosome architecture associates with large offspring syndrome.

Project description:Large offspring syndrome (LOS) and Beckwith-Wiedemann syndrome are similar epigenetic congenital overgrowth conditions in ruminants and humans, respectively. We have reported global loss-of-imprinting, methylome epimutations, and gene misregulation in LOS. However, less than 4% of gene misregulation can be explained with short range (<20kb) alterations in DNA methylation. Therefore, we hypothesized that methylome epimutations in LOS affect chromosome architecture which results in misregulation of genes located at distances >20kb in cis and in trans (other chromosomes). Our analyses focused on two imprinted domains that frequently reveal misregulation in these syndromes, namely KvDMR1 and IGF2R. Using bovine fetal fibroblasts, we identified CTCF binding at IGF2R imprinting control region but not KvDMR1, and allele-specific chromosome architecture of these domains in controls. In LOS, analyses identified erroneous long-range contacts and clustering tendency in the direction of expression of misregulated genes. In conclusion, altered chromosome architecture is associated with LOS.

| S-EPMC9079005 | biostudies-literature

Identification of an evolutionarily conserved cis-regulatory element controlling the Peg3 imprinted domain.

Project description:The mammalian Peg3 domain harbors more than 20 evolutionarily conserved regions (ECRs) that are spread over the 250-kb genomic interval. The majority of these ECRs are marked with two histone modifications, H3K4me1 and H3K27ac, suggesting potential roles as distant regulatory elements for the transcription of the nearby imprinted genes. In the current study, the chromatin conformation capture (3C) method was utilized to detect potential interactions of these ECRs with the imprinted genes. According to the results, one region, ECR18, located 200-kb upstream of Peg3 interacts with the two promoter regions of Peg3 and Zim2. The observed interaction is most prominent in brain, but was also detected in testis. Histone modification and DNA methylation on ECR18 show no allele bias, implying that this region is likely functional on both alleles. In vitro assays also reveal ECR18 as a potential enhancer or repressor for the promoter of Peg3. Overall, these results indicate that the promoters of several imprinted genes in the Peg3 domain interact with one evolutionarily conserved region, ECR18, and further suggest that ECR18 may play key roles in the transcription and imprinting control of the Peg3 domain as a distant regulatory element.

| S-EPMC3769284 | biostudies-literature

Allele-specific aberration of imprinted domain chromosome architecture associates with large offspring syndrome

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-04-22 | GSE197130 | GEO

Allele-specific demethylation at an imprinted mammalian promoter.

Project description:A screen for imprinted genes on mouse Chromosome 7 recently identified Inpp5f_v2, a paternally expressed retrogene lying within an intron of Inpp5f. Here, we identify a novel paternally expressed variant of the Inpp5f gene (Inpp5f_v3) that shows a number of unusual features. Inpp5f_v3 initiates from a CpG-rich repeat region adjoining two B1 elements, despite previous reports that SINEs are generally excluded from imprinted promoters. Accordingly, we find that the Inpp5f_v3 promoter acquires methylation around the time of implantation, when many repeat families undergo de novo epigenetic silencing. Methylation is then lost specifically on the paternally derived allele during the latter stages of embryonic development, resulting in imprinted transcriptional activation on the demethylated allele. Methylation analyses in embryos lacking maternal methylation imprints suggest that the primary imprinting mark resides within an intronic CpG island approximately 1 kb downstream of the Inpp5f_v3 transcriptional start site. These data support the hypothesis that SINEs can influence gene expression by attracting de novo methylation during development, a property likely to explain their exclusion from other imprinted promoters.

| S-EPMC2175309 | biostudies-literature

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