Transcription-driven DNA methylation setting on the mouse <i>Peg3</i> locus

Bretz, Corey L.; Kim, Joomyeong

doi:10.1080/15592294.2017.1377869

Cited by 14 publications

(26 citation statements)

References 22 publications

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“…The transcripts originating here or the process of transcription through the locus is believed to be necessary for the establishment of the maternal methylation imprint [5][6][7]. Similar observations have been made at four other imprinted loci: GNAS/Gnas [8], KCNQ1/Kcnq1 [9][10][11][12], Peg3 [13] and Zrsr1 [14]. Therefore, sequence alterations in the promoter or upstream exons located within the AS-IC might affect transcription in this region and thereby the establishment of the methylation imprint.…”

Section: Introductionmentioning

confidence: 55%

Common genetic variation in the Angelman syndrome imprinting centre affects the imprinting of chromosome 15

et al. 2020

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Angelman syndrome (AS) is a rare neurogenetic imprinting disorder caused by the loss of function of UBE3A. In~3-5% of AS patients, the disease is due to an imprinting defect (ID). These patients lack DNA methylation of the maternal SNRPN promotor so that a large SNRPN sense/UBE3A antisense transcript (SNHG14) is expressed, which silences UBE3A. In very rare cases, the ID is caused by a deletion of the AS imprinting centre (AS-IC). To search for sequence alterations, we sequenced this region in 168 patients without an AS-IC deletion, but did not detect any sequence alteration. However, the AS-IC harbours six common variants (five single nucleotide variants and one TATG insertion/deletion variant), which constitute five common haplotypes. To determine if any of these haplotypes is associated with an increased risk for an ID, we investigated 119 informative AS-ID trios with the transmission disequilibrium test, which is a family-based association test that measures the over-transmission of an allele or haplotype from heterozygous parents to affected offspring. By this we observed maternal over-transmission of haplotype H-AS3 (p = 0.0073). Interestingly, H-AS3 is the only haplotype that includes the TATG deletion allele. We conclude that this haplotype and possibly the TATG deletion, which removes a SOX2 binding site, increases the risk for a maternal ID and AS. Our data strengthen the notion that the AS-IC is important for establishing and/or maintaining DNA methylation at the SNRPN promotor and show that common genetic variation can affect genomic imprinting. 1234567890();,:1234567890();,:

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Section: Introductionmentioning

confidence: 55%

Common genetic variation in the Angelman syndrome imprinting centre affects the imprinting of chromosome 15

et al. 2020

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“…While disruption of imprinting at some maternally silenced genes is associated with severe phenotypic outcomes, consistent with our observations at Slc38a4 and Impact , loss of imprinting and biallelic expression of imprinted genes is not necessarily associated with obvious abnormal phenotypes. Previous studies of the paternally expressed genes Plagl1 3 , Peg3 16 , and Zrsr1 15 for example, revealed only subtle impacts on reproductive fitness following loss of imprinting, although detailed analyses of potential growth-related phenotypes have not always been reported.…”

Section: Discussionmentioning

confidence: 99%

“…This unique class of gDMRs, the imprinted gDMRs (igDMRs), can direct imprinted paternal allele-specific expression of the gene(s) under their regulation, the imprinted genes 3,10,11 . Importantly, transcription initiating within upstream oocyte-specific promoters has been reported to play a critical role in de novo DNAme at the maternal igDMRs of a number of mouse imprinted genes 3,12–16 , but the evolutionary origin of such promoters remains unexplored.…”

Section: Lits and The Establishment Of Species-specific Imprintsmentioning

confidence: 99%

Evolution of imprinting via lineage-specific insertion of retroviral promoters

Bogutz

Brind’Amour

Kobayashi

et al. 2019

Preprint

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26Imprinted genes are expressed from a single parental allele. In mammals, this unusual mode of 27 transcription generally depends on the epigenetic silencing of one allele by DNA methylation 28 (DNAme) established in the germline. While many species-specific imprinted orthologues have been 29 documented in eutherians, the molecular mechanisms underlying the evolutionary switch from biallelic 30 to imprinted expression are currently unknown. During mouse oogenesis, gametic differentially 31 methylated regions (gDMRs) acquire DNAme in a process guided by transcription. Here we show that 32 transcription initiating in proximal lineage-specific endogenous retroviruses (ERVs) is likely 33 responsible for DNAme established in oocytes at 4/6 mouse-specific and 17/110 human-specific 34 maternal imprinted gDMRs (igDMRs). The latter can be further divided into Catarrhini (Old World 35 monkeys and apes)-or Hominoidea (ape)-specific igDMRs, which are embedded within transcription 36 units initiating in ERVs specific to these primate lineages. Using CRISPR-Cas9 mutagenesis, we 37 deleted the relevant murine-specific ERVs upstream of the maternally methylated genes Impact and 38Slc38a4. Strikingly, imprinting at these genes was lost in the offspring of females harboring these 39 deletions and biallelic expression was observed. Our work reveals a novel evolutionary mechanism 40 whereby maternally silenced genes arise from biallelically expressed progenitors. 41 42 43 During postnatal oocyte growth in mammals, transcribed genomic regions acquire two characteristic 44 epigenetic marks: transcription-coupled trimethylation at lysine 36 of histone H3 (H3K36me3) 1 and 45 DNAme 2-5 . In both human and mouse female germline, the overall levels of CpG methylation increase 46 from less than 5% in post-migratory primordial germ cells (PGCs) to ~40-50% in fully-grown, 47 germinal vesicle oocytes (GVOs) 4,6-8 Kobayashi:2013ia}. In growing murine oocytes, 85-90% of this 48 DNAme is deposited over H3K36me3-marked transcribed regions of the genome 3 . Notably, we 49 recently demonstrated that SETD2-dependent deposition of H3K36me3 is required for de novo 50 3 DNAme of transcribed gene bodies in mouse oocytes 9 . Such transcription-coupled de novo DNAme is 51 also responsible for the establishment of regions of differential DNAme between the mature gametes 52 (gametic differentially methylated regions, gDMRs), a subset of which are maintained throughout 53 preimplantation development. This unique class of gDMRs, the imprinted gDMRs (igDMRs), can 54 direct imprinted paternal allele-specific expression of the gene(s) under their regulation, the imprinted 55 genes 3,10,11 . Importantly, transcription initiating within upstream oocyte-specific promoters has been 56 reported to play a critical role in de novo DNAme at the maternal igDMRs of a number of mouse 57 imprinted genes 3,12-16 , but the evolutionary origin of such promoters remains unexplored. 58 59 Specific families of ERVs, also known as long terminal repeat (LTR) retrotransposons, are 6...

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“…To identify these alternative promoters for the Peg3 domain, we previously performed several sets of Next Generation Sequencing (NGS)-based Rapid Amplification of cDNA Ends (RACE) experiments [ 17 , 18 ]. Indeed, one of the identified alternative promoters, termed U1, is involved in establishing DNA methylation on the ICR of the Peg3 domain [ 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

Circular RNA identified from Peg3 and Igf2r

2018

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Circular RNA is a newly discovered class of non-coding RNA generated through the back-splicing of linear pre-mRNA. In the current study, we characterized two circular RNAs that had been identified through NGS-based 5’RACE experiments. According to the results, the Peg3 locus contains a 214-nucleotide-long circular RNA, circPeg3, that is detected in low abundance from the neonatal brain, lung and ovary. In contrast, the Igf2r locus contains a group of highly abundant circular RNAs, circIgf2r, showing multiple forms with various exon combinations. In both cases, the expression patterns of circPeg3 and circIgf2r among individual tissues are quite different from their linear mRNA counterparts. This suggests potential unique roles played by the identified circular RNAs. Overall, this study reports the identification of novel circular RNAs specific to mammalian imprinted loci, suggesting that circular RNAs are likely involved in the function and regulation of imprinted genes.

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Transcription-driven DNA methylation setting on the mouse Peg3 locus

Cited by 14 publications

References 22 publications

Common genetic variation in the Angelman syndrome imprinting centre affects the imprinting of chromosome 15

Common genetic variation in the Angelman syndrome imprinting centre affects the imprinting of chromosome 15

Evolution of imprinting via lineage-specific insertion of retroviral promoters

Circular RNA identified from Peg3 and Igf2r

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