Biallelic expression of imprinted genes in the mouse germ line: implications for erasure, establishment, and mechanisms of genomic imprinting.

Szabó, Piroska E.; Mann, Jeffrey R.

doi:10.1101/gad.9.15.1857

Cited by 247 publications

(142 citation statements)

References 72 publications

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“…The expression pattern of the hum an IG F2R gene at earlier stages of development is still unknown. In the mouse, both maternal and paternal Ig f2 r alleles are expressed during preimplantation development (Latham et al, 1994;Szabo and Mann, 1995), indicating that in this species, monoallelic expression is due to secondary in activation of one Ig f2 r gene copy. Along these lines, biallelic expression of the hum an IG F2R gene might result from failing repression of the paternal allele.…”

Section: Cpg 1 Is Completely Unmethylated On Both Parental Igf2r Allementioning

confidence: 99%

Maternal-Specific Methylation of the HumanIGF2RGene Is Not Accompanied by Allele-Specific Transcription

et al. 1996

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The hum an in su lin -lik e grow th factor type 2 recep tor gen e (IGF2R) is b ia llelica lly expressed in a variety o f fetal and adult tissu es. In contrast, the im printed m ouse Igf2r gen e is exp ressed exclu sively from the ma ternally in h erited chrom osom e. The m ouse gene con tains tw o CpG isla n d s th at are m ethylated in a parentspecific m anner. M éthylation o f th e CpG island in the prom oter region occu rs on th e repressed paternal gene copy. M éthylation of th e CpG island in intron 2 is specific for th e a ctiv e m aternal allele and m ay repre sen t the prim ary im print. H ere, we have analyzed the hum an IGF2R gen e to in v estig a te w hether these m otifs and th eir parent-of-origin-specific epigenetic modifi cation have b een conserved. As in th e mouse, the hu man IGF2R gen e w as found to contain two CpG is lands, one en com p assin g th e transcription start site (CpG 1) and th e oth er in th e second intron (CpG 2). CpG 2 is h yp erm eth ylated on th e m aternal IGF2R al lele. In contrast to th e situ a tio n in th e m ouse, how ever, the hum an CpG 1 is com p letely unm ethylated on both parental chrom osom es, The hum an and m ouse intronic CpG islan d s la ck sign ifican t sequence hom ol ogy* w h ich su g g ests th a t DNA conform ation plays a role in allele-Specific m éthylation.

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Section: Cpg 1 Is Completely Unmethylated On Both Parental Igf2r Allementioning

confidence: 99%

Maternal-Specific Methylation of the HumanIGF2RGene Is Not Accompanied by Allele-Specific Transcription

et al. 1996

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“…A 10-g aliquot of total RNA was loaded per lane. Allele-specific expression was determined using reverse transcription-PCR single-nucleotide primer extension assays as described previously (40,41). Each assay relies on a single known sequence difference between allelic RNAs.…”

Section: Methodsmentioning

confidence: 99%

“…Males homozygous for the mutant ICR (Ϫ/Ϫ) were mated to normal CF1 females (Charles River), and the resulting adult ϩ/Ϫ females were superovulated (11). Oocyte collection was done as published previously (40). Four separate bisulfite reactions were done on pools of 190, 150, 175, and 175 oocytes embedded into agarose beads (25), and each reaction was PCR amplified separately.…”

Section: Dna Methylation Of the Icr In Germ Cells (I) Perinatal Germmentioning

confidence: 99%

Role of CTCF Binding Sites in the Igf2/H19 Imprinting Control Region

Szabó

Tang

Silva

et al. 2004

Molecular and Cellular Biology

130

165

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A ϳ2.4-kb imprinting control region (ICR) regulates somatic monoallelic expression of the Igf2 and H19 genes. This is achieved through DNA methylation-dependent chromatin insulator and promoter silencing activities on the maternal and paternal chromosomes, respectively. In somatic cells, the hypomethylated maternally inherited ICR binds the insulator protein CTCF at four sites and blocks activity of the proximal Igf2 promoter by insulating it from its distal enhancers. CTCF binding is thought to play a direct role in inhibiting methylation of the ICR in female germ cells and in somatic cells and, therefore, in establishing and maintaining imprinting of the Igf2/H19 region. Here, we report on the effects of eliminating ICR CTCF binding by severely mutating all four sites in mice. We found that in the female and male germ lines, the mutant ICR remained hypomethylated and hypermethylated, respectively, showing that the CTCF binding sites are dispensable for imprinting establishment. Postfertilization, the maternal mutant ICR acquired methylation, which could be explained by loss of methylation inhibition, which is normally provided by CTCF binding. Adjacent regions in cis-the H19 promoter and gene-also acquired methylation, accompanied by downregulation of H19. This could be the result of a silencing effect of the methylated maternal ICR.

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“…Differential methylation of cytosine residues in CpG dinucleotides in critical regions of imprinted genes is part of the imprinting process differentiating paternal and maternal alleles (Barlow, 1993). Imprinted genes have been well analysed in terms of genome reprogramming, and it is widely accepted that imprinting memories are erased in PGCs and that DNA methylation is an important factor in this process (Grant et al, 1992;Kafri et al, 1992;Brandeis et al, 1993;Szabo and Mann, 1995b;Kato et al, 1999). Maternally expressed H19 is one of the best-characterized imprinted genes.…”

Section: Introductionmentioning

confidence: 99%

“…Takai et al (2001) have shown that only the sixth of the seven CTCF-binding sites demonstrates allele-specific methylation. Expression of imprinted genes, such as H19, in the germ line become biallelic at day 11.5 of mouse embryonic development (Szabo and Mann, 1995b;Villar et al, 1995). Loss of allele-specific methylation imprints has also been observed in both male and female PGCs of the mouse (Tada et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Erasure of methylation imprint at the promoter and CTCF-binding site upstream of H19 in human testicular germ cell tumors of adolescents indicate their fetal germ cell origin

et al. 2006

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Genome-wide epigenetic modification plays a crucial role in regulating genome functions at critical stages of development. In particular, DNA methylation is known to be reprogrammed on a genome-wide level in germ cells and in preimplantation embryos, although it is relatively stable in somatic cells. In this reprogramming process, the genome becomes demethylated, and methylated de novo during later stages of development. Reprogramming of DNA methylation in male germ cells has not been fully investigated. Testicular germ cell tumors (TGCTs) possess a pluripotential nature and display protean histology from germ cells to embryonal and somatic cell differentiation. These properties make TGCT a unique model for studying germ cell development and gametogenesis in respect of DNA reprogramming. In order to obtain an insight into the epigenetic dynamics of TGCTs, we conducted a comprehensive analysis of differential methylated regions (DMRs) on H19 and IGF2 in TGCTs compared with testicular malignant lymphomas. In the present study, we show that methylation imprint at the promoter and CTCF-binding site upstream of H19 was completely erased in both seiminomatous and nonseminomatous TGCTs, whereas differential methylation was observed in testicular lymphomas. The erasure of methylation imprint was also observed in TGCTs with malignant transformation. We found biallelic unmethylation at the promoter and the CTCF-binding site upstream of H19 is required, but not sufficient for the biallelic expression of H19 in TGCTs. These data suggest that factors other than methylation contribute to transcriptional regulation of imprinted genes in TGCTs. The present data have shown that TGCTs carry distinctive epigenetic profiles at the core-imprinting domain of H19/ IGF2 from other neoplasms of somatic cell origin. The data also suggest that both seminomatous and nonseminomatous TGCTs carry methylation profiles similar to fetal germ cells, but not adult germ cells, indicating the origin of TGCTs as fetal germ cells.

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Biallelic expression of imprinted genes in the mouse germ line: implications for erasure, establishment, and mechanisms of genomic imprinting.

Cited by 247 publications

References 72 publications

Maternal-Specific Methylation of the HumanIGF2RGene Is Not Accompanied by Allele-Specific Transcription

Maternal-Specific Methylation of the HumanIGF2RGene Is Not Accompanied by Allele-Specific Transcription

Role of CTCF Binding Sites in the Igf2/H19 Imprinting Control Region

Erasure of methylation imprint at the promoter and CTCF-binding site upstream of H19 in human testicular germ cell tumors of adolescents indicate their fetal germ cell origin

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