Sexual Dimorphism of Genes Implicated in Epigenetic Regulation in Early Mouse Development.
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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)Keywords:
DNMT3B
Epigenome
Reprogramming
DNA demethylation
XIST
Dosage compensation
Housekeeping gene
Inner cell mass
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Dosage compensation
Gene dosage
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Dosage compensation
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ABSTRACT By transcribing XIST RNA, the human inactive X chromosome has a prime role in X-dosage compensation. Yet, the autosomes also play an important role in the process. In fact, multiple genes on human chromosome 1 interact with XIST RNA to silence the inactive Xs, no matter how many there are. And it is likely that multiple genes on human chromosome 19 prevent the silencing of the single active X, which is a highly dosage sensitive process. Previous studies of the organization of chromosomes in the nucleus and their genomic interactions indicate that most contacts are intra-chromosomal. Coordinate transcription or dosage regulation could explain the clustered organization of these autosomal genes on these two chromosomes that are critical for X dosage compensation in human cells. Unlike those on chromosome 1, the genes within the critical eight MB region of chromosome 19, have remained together in all mammals assayed, except rodents, indicating that their proximity in non-rodent mammals is evolutionarily conserved.
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Dosage compensation
Skewed X-inactivation
Gene dosage
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X chromosome inactivation achieves dosage equivalence for most X-linked genes between the two X chromosomes in females and the single X chromosome in males. In this article the evidence for random inactivation of an X chromosome is reviewed, along with the exceptions that result in nonrandom inactivation. Another exception to X chromosome inactivation is the presence of genes that escape inactivation and are expressed from both the active and inactive X chromosomes. The phenotypic consequences of such expression from the inactive X chromosome are discussed. The major players in the process of inactivation are presented. Initiation of inactivation requires the functional RNA, XIST, and the subsequent stable inactivation of the X chromosome relies upon the recruitment of many other factors, the majority of which are generally associated with heterochromatin.
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X-chromosome inactivation (XCI) compensates for differences in X-chromosome number between male and female mammals. XCI is orchestrated by Xist RNA, whose expression in early development leads to transcriptional silencing of one X chromosome in the female. Knockout studies have established a requirement for Xist with inviability of female embryos that inherit an Xist deletion from the father. Here, we report that female mice lacking Xist RNA can, surprisingly, develop and survive to term. Xist -null females are born at lower frequency and are smaller at birth, but organogenesis is mostly normal. Transcriptomic analysis indicates significant overexpression of hundreds of X-linked genes across multiple tissues. Therefore, Xist -null mice can develop to term in spite of a deficiency of dosage compensation. However, the degree of X-autosomal dosage imbalance was less than anticipated (1.14-fold to 1.36-fold). Thus, partial dosage compensation can be achieved without Xist , supporting the idea of inherent genome balance. Nevertheless, to date, none of the mutant mice has survived beyond weaning stage. Sudden death is associated with failure of postnatal organ maturation. Our data suggest Xist-independent mechanisms of dosage compensation and demonstrate that small deviations from X-autosomal balance can have profound effects on overall fitness.
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Abstract Dosage compensation is the process by which the amount of X‐linked gene products between individuals with one and two X chromosomes is equalized. In mammals, dosage compensation is achieved by the transcriptional silencing of one X chromosome in female cells. Inactivation is attained by the establishment of several sequential epigenetic modifications in the future inactive X triggered by expression of the Xist gene in cis, and including different histone modifications and methylation of CpG islands. These transformations occur during early embryonic development and require that the cell counts the X chromosomes and chooses one to be active per diploid genome, inactivating the others. Here, we will review what is currently known about the early events of X‐chromosome inactivation, and discuss the mechanisms by which a cell counts and chooses X chromosomes.
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Dosage compensation is the process by which the levels of X-linked gene expression is equalized between the sexes.In mammals,it is achieved by random inactivating one of the two X chromosomes in the female.X inactivation starts at the X-inactivation center(XIC) and spreads throughout the chromosomes.The Xist gene maps to the XIC region on the X chromosome and is thought to be involved in the initiation of inactivation.X-linked gene expression in androgenones,gynogenones,parthenogenones and normal Embryos were analysed in this article;Whilst it also summaried the effect of X chromosome inactivation(XIC) on the development of early embryos in mammals,and reviewed the dosage compensation of early embryo and its effect on the development in mammals
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Dosage compensation
Gene dosage
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