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Human imprinted retrogenes exhibit non-canonical imprint chromatin signatures and reside in non-imprinted host genes.

Monk D, Arnaud P, Frost JM, Wood AJ, Cowley M, Martin-Trujillo A, Guillaumet-Adkins A, Iglesias Platas I, Camprubi C, Bourc'his D, Feil R, Moore GE, Oakey RJ - Nucleic Acids Res. (2011)

Bottom Line: Imprinted retrotransposed genes share a common genomic organization including a promoter-associated differentially methylated region (DMR) and a position within the intron of a multi-exonic 'host' gene.To address the mechanisms governing imprinted retrogene expression, histone modifications were assayed at the DMRs.Two human retrogenes showed monoallelic enrichment of active, but not of repressive marks suggesting a partial uncoupling of the relationship between DNA methylation and repressive histone methylation, possibly due to the smaller size and lower CpG density of these DMRs.

View Article: PubMed Central - PubMed

Affiliation: Imprinting and Cancer Group, Cancer Epigenetics and Biology Program, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet de Llobregat, 08907, Barcelona, Spain. dmonk@iconcologia.net

ABSTRACT
Imprinted retrotransposed genes share a common genomic organization including a promoter-associated differentially methylated region (DMR) and a position within the intron of a multi-exonic 'host' gene. In the mouse, at least one transcript of the host gene is also subject to genomic imprinting. Human retrogene orthologues are imprinted and we reveal that human host genes are not imprinted. This coincides with genomic rearrangements that occurred during primate evolution, which increase the separation between the retrogene DMRs and the host genes. To address the mechanisms governing imprinted retrogene expression, histone modifications were assayed at the DMRs. For the mouse retrogenes, the active mark H3K4me2 was associated with the unmethylated paternal allele, while the methylated maternal allele was enriched in repressive marks including H3K9me3 and H4K20me3. Two human retrogenes showed monoallelic enrichment of active, but not of repressive marks suggesting a partial uncoupling of the relationship between DNA methylation and repressive histone methylation, possibly due to the smaller size and lower CpG density of these DMRs. Finally, we show that the genes immediately flanking the host genes in mouse and human are biallelically expressed in a range of tissues, suggesting that these loci are distinct from large imprinted clusters.

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(A) A schematic map of the Abcg2 gene, with the location of the alternative promoter regions. The methylation status of the CpG island associated with isoform 1 was examined in placenta-derived DNA. The allelic expression of Abcg2 is assessed in various fetal tissues in reciprocal mouse crosses. (B) The allelic expression of Abcg2 and Nap1l5 in placental trophoblasts from Dnmt3l−/+ mice. (C) The allelic expression of the ABCG2 gene in human term placenta.
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Figure 2: (A) A schematic map of the Abcg2 gene, with the location of the alternative promoter regions. The methylation status of the CpG island associated with isoform 1 was examined in placenta-derived DNA. The allelic expression of Abcg2 is assessed in various fetal tissues in reciprocal mouse crosses. (B) The allelic expression of Abcg2 and Nap1l5 in placental trophoblasts from Dnmt3l−/+ mice. (C) The allelic expression of the ABCG2 gene in human term placenta.

Mentions: In order to determine the boundaries of imprinting at each retrogene-host locus, we investigated the allele-specific expression of the genes flanking the host genes in both mice and humans. We assessed expression in various embryonic tissues and placenta using allele-specific assays between crosses of mouse strains C57BL/6 (B) x Mus musculus castaneus (C). The genes immediately adjacent to Mcts2/H13, Id1 and Remi, are biallelically expressed in all tissues at embryonic day E18.5, as are 111007A13RIK and Bag3 flanking Inpp5f_v2/Inpp5f. The Fam13a gene, telomeric to Nap1l5/Herc3 is expressed from both alleles, while Abcg2, centromeric to Nap1l5/Herc3, is monoallelically expressed in the placenta. This reflects a bias in expression from the C57BL/6 allele and the gene is therefore an expressed quantitative trait locus (eQTL) and not imprinted (Figure 2A and Supplementary Figure S2). This conclusion is supported by the persistence of Abcg2 monoallelic expression in Dnmt3l−/+ placental trophoblast, despite the loss of imprinting of Nap1l5 (Figure 2B).Figure 2.


Human imprinted retrogenes exhibit non-canonical imprint chromatin signatures and reside in non-imprinted host genes.

Monk D, Arnaud P, Frost JM, Wood AJ, Cowley M, Martin-Trujillo A, Guillaumet-Adkins A, Iglesias Platas I, Camprubi C, Bourc'his D, Feil R, Moore GE, Oakey RJ - Nucleic Acids Res. (2011)

(A) A schematic map of the Abcg2 gene, with the location of the alternative promoter regions. The methylation status of the CpG island associated with isoform 1 was examined in placenta-derived DNA. The allelic expression of Abcg2 is assessed in various fetal tissues in reciprocal mouse crosses. (B) The allelic expression of Abcg2 and Nap1l5 in placental trophoblasts from Dnmt3l−/+ mice. (C) The allelic expression of the ABCG2 gene in human term placenta.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3113556&req=5

Figure 2: (A) A schematic map of the Abcg2 gene, with the location of the alternative promoter regions. The methylation status of the CpG island associated with isoform 1 was examined in placenta-derived DNA. The allelic expression of Abcg2 is assessed in various fetal tissues in reciprocal mouse crosses. (B) The allelic expression of Abcg2 and Nap1l5 in placental trophoblasts from Dnmt3l−/+ mice. (C) The allelic expression of the ABCG2 gene in human term placenta.
Mentions: In order to determine the boundaries of imprinting at each retrogene-host locus, we investigated the allele-specific expression of the genes flanking the host genes in both mice and humans. We assessed expression in various embryonic tissues and placenta using allele-specific assays between crosses of mouse strains C57BL/6 (B) x Mus musculus castaneus (C). The genes immediately adjacent to Mcts2/H13, Id1 and Remi, are biallelically expressed in all tissues at embryonic day E18.5, as are 111007A13RIK and Bag3 flanking Inpp5f_v2/Inpp5f. The Fam13a gene, telomeric to Nap1l5/Herc3 is expressed from both alleles, while Abcg2, centromeric to Nap1l5/Herc3, is monoallelically expressed in the placenta. This reflects a bias in expression from the C57BL/6 allele and the gene is therefore an expressed quantitative trait locus (eQTL) and not imprinted (Figure 2A and Supplementary Figure S2). This conclusion is supported by the persistence of Abcg2 monoallelic expression in Dnmt3l−/+ placental trophoblast, despite the loss of imprinting of Nap1l5 (Figure 2B).Figure 2.

Bottom Line: Imprinted retrotransposed genes share a common genomic organization including a promoter-associated differentially methylated region (DMR) and a position within the intron of a multi-exonic 'host' gene.To address the mechanisms governing imprinted retrogene expression, histone modifications were assayed at the DMRs.Two human retrogenes showed monoallelic enrichment of active, but not of repressive marks suggesting a partial uncoupling of the relationship between DNA methylation and repressive histone methylation, possibly due to the smaller size and lower CpG density of these DMRs.

View Article: PubMed Central - PubMed

Affiliation: Imprinting and Cancer Group, Cancer Epigenetics and Biology Program, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet de Llobregat, 08907, Barcelona, Spain. dmonk@iconcologia.net

ABSTRACT
Imprinted retrotransposed genes share a common genomic organization including a promoter-associated differentially methylated region (DMR) and a position within the intron of a multi-exonic 'host' gene. In the mouse, at least one transcript of the host gene is also subject to genomic imprinting. Human retrogene orthologues are imprinted and we reveal that human host genes are not imprinted. This coincides with genomic rearrangements that occurred during primate evolution, which increase the separation between the retrogene DMRs and the host genes. To address the mechanisms governing imprinted retrogene expression, histone modifications were assayed at the DMRs. For the mouse retrogenes, the active mark H3K4me2 was associated with the unmethylated paternal allele, while the methylated maternal allele was enriched in repressive marks including H3K9me3 and H4K20me3. Two human retrogenes showed monoallelic enrichment of active, but not of repressive marks suggesting a partial uncoupling of the relationship between DNA methylation and repressive histone methylation, possibly due to the smaller size and lower CpG density of these DMRs. Finally, we show that the genes immediately flanking the host genes in mouse and human are biallelically expressed in a range of tissues, suggesting that these loci are distinct from large imprinted clusters.

Show MeSH
Related in: MedlinePlus