Dataset Information

The origin of the RB1 imprint.

ABSTRACT: The human RB1 gene is imprinted due to a differentially methylated CpG island in intron 2. This CpG island is part of PPP1R26P1, a truncated retrocopy of PPP1R26, and serves as a promoter for an alternative RB1 transcript. We show here by in silico analyses that the parental PPP1R26 gene is present in the analysed members of Haplorrhini, which comprise Catarrhini (Old World Monkeys, Small apes, Great Apes and Human), Platyrrhini (New World Monkeys) and tarsier, and Strepsirrhini (galago). Interestingly, we detected the retrocopy, PPP1R26P1, in all Anthropoidea (Catarrhini and Platyrrhini) that we studied but not in tarsier or galago. Additional retrocopies are present in human and chimpanzee on chromosome 22, but their distinct composition indicates that they are the result of independent retrotransposition events. Chimpanzee and marmoset have further retrocopies on chromosome 8 and chromosome 4, respectively. To examine the origin of the RB1 imprint, we compared the methylation patterns of the parental PPP1R26 gene and its retrocopies in different primates (human, chimpanzee, orangutan, rhesus macaque, marmoset and galago). Methylation analysis by deep bisulfite sequencing showed that PPP1R26 is methylated whereas the retrocopy in RB1 intron 2 is differentially methylated in all primates studied. All other retrocopies are fully methylated, except for the additional retrocopy on marmoset chromosome 4, which is also differentially methylated. Using an informative SNP for the methylation analysis in marmoset, we could show that the differential methylation pattern of the retrocopy on chromosome 4 is allele-specific. We conclude that the epigenetic fate of a PPP1R26 retrocopy after integration depends on the DNA sequence and selective forces at the integration site.

SUBMITTER: Kanber D

PROVIDER: S-EPMC3839921 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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The origin of the RB1 imprint.

Kanber Deniz D Buiting Karin K Roos Christian C Gromoll Jörg J Kaya Sabine S Horsthemke Bernhard B Lohmann Dietmar D

PloS one 20131125 11

The human RB1 gene is imprinted due to a differentially methylated CpG island in intron 2. This CpG island is part of PPP1R26P1, a truncated retrocopy of PPP1R26, and serves as a promoter for an alternative RB1 transcript. We show here by in silico analyses that the parental PPP1R26 gene is present in the analysed members of Haplorrhini, which comprise Catarrhini (Old World Monkeys, Small apes, Great Apes and Human), Platyrrhini (New World Monkeys) and tarsier, and Strepsirrhini (galago). Intere ...[more]

PMID: 24282601

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Project description:Retinoblastoma (Rb), the most common pediatric intraocular neoplasm, results from inactivation of both alleles of the RB1 tumor suppressor gene. The second allele is most commonly lost, as demonstrated by loss of heterozygosity studies. RB1 germline carriers usually develop bilateral tumors, but some Rb families display low penetrance and variable expressivity. In order to decipher the underlying mechanisms, 23 unrelated low penetrance pedigrees segregating the common c.1981C>T/p.Arg661Trp mutation and other low penetrance mutations were studied. In families segregating the c.1981C>T mutation, we demonstrated, for the first time, a correlation between the gender of the transmitting carrier and penetrance, as evidenced by Fisher's exact test: the probability of being unaffected is 90.3% and 32.5% when the mutation is inherited from the mother and the father, respectively (p-value = 7.10(-7). Interestingly, a similar correlation was observed in families segregating other low penetrance alleles. Consequently, we investigated the putative involvement of an imprinted, modifier gene in low penetrance Rb. We first ruled out a MED4-driven mechanism by MED4 methylation and expression analyses. We then focused on the differentially methylated CpG85 island located in intron 2 of RB1 and showing parent-of-origin-specific DNA methylation. This differential methylation promotes expression of the maternal c.1981C>T allele. We propose that the maternally inherited c.1981C>T/p.Arg661Trp allele retains sufficient tumor suppressor activity to prevent retinoblastoma development. In contrast, when the mutation is paternally transmitted, the low residual activity would mimic a null mutation and subsequently lead to retinoblastoma. This implies that the c.1981C>T mutation is not deleterious per se but needs to be destabilized in order to reach pRb haploinsufficiency and initiate tumorigenesis. We suggest that this phenomenon might be a general mechanism to explain phenotypic differences in low penetrance Rb families.

Dataset Information

The origin of the RB1 imprint.

Publications

The origin of the RB1 imprint.

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