Notes on the epigenetic origins of childhood cancer.
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Preimplantation development is a key period for the establishment of epigenetic marks, as complete epigenetic reprogramming involving DNA methylation and histone modifications occurs from the gametes to the blastocyst stage. The changing epigenetic landscape makes preimplantation embryos especially vulnerable to modifications of the epigenome initiated by assisted reproduction techniques or factors, such as maternal diet and exposure to toxic compounds. Such changes may result in long term developmental and health consequences for the offspring, which can be manifested in a sex-specific manner. Additionally, preimplantation bovine embryos are known to display sexual dimorphism in transcription of certain genes with roles in DNA methylation and regulation of transcription, and these differences correlate with the extent of methylation of specific sequences. The aim of this study has been to compare the sex-related differences in the expression of nine genes implicated in epigenetic regulation in mouse blastocysts. In vivo derived blastocysts were obtained from CD1 females mated with Tg(CAG-EGFP)D4Nagy/J males, which have a copy of a GFP gene inserted into their X chromosome, thereby allowing males and females to be distinguished under a fluorescent microscope. Five groups of 10 embryos of each sex were used in the analyses. PolyA RNA was extracted by Dynabeads. After revese transcription, mRNA abundance relative to the housekeeping gene, H2afz, was obtained by qPCR. The genes analyzed were related with maintenance (Dnmt1) or de novo (Dnmt3a and Dnmt3b) DNA methylation, DNA demethylation (Mbd2 and Mbd3), and two pairs of sex chromosome encoded genes related with histone demethylation of H3K27 (Kdm6a -- previously known as Utx- and Uty) and H3K4 (Kdm5c -- previously known as Jarid1c- and Kdm5d -- Jarid1d-). The expression level of the 4 genes with roles in DNA methylation did not differ between sexes. However, the two X-linked genes, Kdm6a and Kdm5c, escaped X inactivation and were overexpressed in females (ANOVA P<0.05; male vs female, mean ± SEM; Kdm6a 1 ± 0.1 vs 1.83 ± 0.1; Kdm5c 1 ± 0.1 vs 1.54 ± 0.1); whereas, the expression of the two Y-linked (Uty and Kdm5d) genes was, as expected, restricted to males. The mRNA and protein sequences of both gene pairs and their proteins have diverged over evolution, specially in the case of KDM6A/UTY (KDM5C/KDM5D proteins 80% identity, 95% coverage; KDM6A/UTY proteins 77% identity, 85% coverage), which may indicate a functional divergence. Interestingly, H3K27me3 is involved in X-chromosome inactivation and, recently, it has been proposed to exert a major role in ICM/TE differentiation and ES derivation. The sexually dimorphic patterns in the expression of these genes may explain the differences in susceptibilities to epigenetic modifications between male and female embryos, and a possible effect of sex chromosome dosage on pluripotency and differentiation.Supported by HD21896 to RMR and RC1 ES018195 to CSR. (poster)
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DNA demethylation
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Housekeeping gene
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Journal Article A Taql polymorphism detected by a genomic clone at the locus D5S39 (5q11–13) Get access B.S. Mankoo, B.S. Mankoo Department of Academic Psychiatry, University College and Middlesex School of MedicineRiding House Street, London W1N 8AA, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar G. Melmer, G. Melmer Department of Academic Psychiatry, University College and Middlesex School of MedicineRiding House Street, London W1N 8AA, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar G. Kalsi, G. Kalsi Department of Academic Psychiatry, University College and Middlesex School of MedicineRiding House Street, London W1N 8AA, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar R. Sherrington, R. Sherrington Department of Academic Psychiatry, University College and Middlesex School of MedicineRiding House Street, London W1N 8AA, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar H.M.D. Gurling H.M.D. Gurling Department of Academic Psychiatry, University College and Middlesex School of MedicineRiding House Street, London W1N 8AA, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar Nucleic Acids Research, Volume 19, Issue 7, 11 April 1991, Page 1720, https://doi.org/10.1093/nar/19.7.1720 Published: 11 April 1991
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Arabidopsis DNA hypomethylation mutation, ddm1 , results in a variety of developmental abnormalities by slowly inducing heritable lesions at unlinked loci. Here, late‐flowering traits observed at high frequencies in independently‐established ddm1 lines were genetically characterized. In all of the four late‐flowering lines examined the traits were dominant and mapped to the same chromosomal region, which is close or possibly identical to the FWA locus. The ddm1 ‐induced phenotypic onsets are apparently not random mutation events, but specific to a group of genes, suggesting the underlying epigenetic mechanism. The DNA methylation mutant provide useful system for identifying epigenetically‐regulated genes important for plant development.
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