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Results for “noncoding RNA”
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The Polycomb group protein Eed protects the inactive X-chromosome from differentiation-induced reactivation.
The Polycomb group (PcG) encodes an evolutionarily conserved set of chromatin-modifying proteins that are thought to maintain cellular transcriptional memory by stably silencing gene expression. In mouse embryos that are mutated for the PcG protein Eed, X-chromosome inactivation (XCI) is not stably maintained in extra-embryonic tissues. Eed is a component of a histone-methyltransferase complex that is thought to contribute to stable silencing in undifferentiated cells due to its enrichment on the inactive X-chromosome in cells of the early mouse embryo and in stem cells of the extra-embryonic trophectoderm lineage. Here, we demonstrate that the inactive X-chromosome in Eed(-/-) trophoblast stem cells and in cells of the trophectoderm-derived extra-embryonic ectoderm in Eed(-/-) embryos remain transcriptionally silent, despite lacking the PcG-mediated histone modifications that normally characterize the facultative heterochromatin of the inactive X-chromosome. Whereas undifferentiated Eed(-/-) trophoblast stem cells maintained XCI, reactivation of the inactive X-chromosome occurred when these cells were differentiated. These results indicate that PcG complexes are not necessary to maintain transcriptional silencing of the inactive X-chromosome in undifferentiated stem cells. Instead, PcG proteins seem to propagate cellular memory by preventing transcriptional activation of facultative heterochromatin during differentiation.
Transient colocalization of X-inactivation centres accompanies the initiation of X inactivation.
The initial differential treatment of the two X chromosomes during X-chromosome inactivation is controlled by the X-inactivation centre (Xic). This locus determines how many X chromosomes are present in a cell ('counting') and which X chromosome will be inactivated in female cells ('choice'). Critical control sequences in the Xic include the non-coding RNAs Xist and Tsix, and long-range chromatin elements. However, little is known about the process that ensures that X inactivation is triggered appropriately when more than one Xic is present in a cell. Using three-dimensional fluorescence in situ hybridization (FISH) analysis, we showed that the two Xics transiently colocalize, just before X inactivation, in differentiating female embryonic stem cells. Using Xic transgenes capable of imprinted but not random X inactivation, and Xic deletions that disrupt random X inactivation, we demonstrated that Xic colocalization is linked to Xic function in random X inactivation. Both long-range sequences and the Tsix element, which generates the antisense transcript to Xist, are required for the transient interaction of Xics. We propose that transient colocalization of Xics may be necessary for a cell to determine Xic number and to ensure the correct initiation of X inactivation.
Is Tsix repression of Xist specific to mouse?
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Gamete-specific methylation correlates with imprinting of the murine Xist gene.
We have investigated the potential role of DNA methylation as a regulator of imprinted Xist expression in mouse preimplantation embryos. The active paternal allele was found to be unmodified in sperm at CpG loci near the 5' end of the gene transcription unit. In contrast, on the inactive maternal allele, these same sites are initially methylated in the oocyte and then remain modified in the early embryo. In the male germ line, these methyl moieties are removed during spermatogenesis, and this occurs before the programmed reactivation of Xist in the testis. This represents a clear-cut example of a potential methylation imprinting signal that is reprogrammable and gamete derived.
Methylation of the mouse Xist gene in sperm and eggs correlates with imprinted Xist expression and paternal X-inactivation.
Preferential paternal X-inactivation in the extra-embryonic tissues of the female mouse embryo is correlated with imprinted expression of the paternal allele of the Xist gene in pre-implantation development. Here we examine 11 CpG sites in Xist to determine whether differential methylation might be the molecular basis for imprinting. We find that three sites in the promoter region are methylated in eggs but not in sperm and that this differential methylation is maintained to the blastocyst stage when the paternal X-inactivation occurs. This is the first example of a primary gametic methylation imprint governing differential expression of parental alleles in pre-implantation embryos.
Deregulation of both imprinted and expressed alleles of the insulin-like growth factor 2 gene during beta-cell tumorigenesis.
In a mouse model of multistage carcinogenesis elicited by the SV40 large T-antigen (Tag) oncogene in pancreatic beta cells, the gene for insulin-like growth factor IGF2 is focally up-regulated and functionally implicated in tumour development. The IGF2 gene is differentially regulated in normal tissues: the paternal allele is transiently expressed during embryogenesis, whereas the maternal allele is genomically imprinted and inactive. Crossbred mice carrying the Tag oncogene and a disruption of either the paternal or maternal allele of IGF2 reveal that both alleles are co-activated early during tumour development, and that each contributes to malignant hyperproliferation and consequent tumour volume.
An imprinting element from the mouse H19 locus functions as a silencer in Drosophila.
Genomic imprinting as originally described in Sciara is displayed by many organisms. In mammals, X-inactivation and the parent-of-origin-specific silencing of imprinted genes are examples of this phenomenon. A heritable chromatin structural modification may be the critical mechanism in such instances of chromosome condensation and preferential gene inactivation. H19 is an imprinted gene in which the repressed paternal allele is hypermethylated and the compacted chromatin is relatively resistant to digestion by nucleases. In order to uncover underlying conserved epigenetic mechanisms we have introduced a mouse H19 transgene into Drosophila. We show here that a 1.2-kb H19 upstream sequence functions in cis as a parent-of-origin independent silencing element in Drosophila. Strikingly, this cis-acting element is located within an upstream region that is necessary for H19 imprinting in mice. These results suggest involvement of an evolutionary conserved mechanism in both genes silencing in Drosophila and imprinting in mice.
If it's not one thing, it's another.
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Establishment of functional imprinting of the H19 gene in human developing placentae.
We have found that the imprinted H19 gene can be expressed either biallelically or monoallelically in the developing human placentae. H19 biallelic expression is confined to the placenta until 10 weeks of gestation, after which it becomes exclusively maternal, and does not affect allele-specificity or levels of IGF2 expression. The promoter region of H19 is hypomethylated at all stages of placental development, while the 3' portion shows progressive methylation of the paternal allele with gestation. Our observations demonstrate that the establishment of functional H19 imprinting occurs during the early development of the placenta and provide an opportunity to understand the mechanism by which the H19 primary imprint is manifested in somatic cells.
Shifting insulator boundaries.
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CTCF maintains differential methylation at the Igf2/H19 locus.
Genomic imprinting relies on establishing and maintaining the parental-specific methylation of DNA elements that control the differential expression of maternal and paternal alleles. Although the essential DNA methyltransferases have been discovered, proteins that regulate the sequence-specific establishment and maintenance of allelic methylation have not been identified. One candidate regulator of methylation, the zinc-finger protein CTCF, binds to the imprinting control region (ICR) of the genes Igf2 (encoding insulin-like growth factor 2) and H19 (fetal liver mRNA; refs. 1,2). The unmethylated maternal ICR is a chromatin boundary that prevents distant enhancers from activating Igf2 (refs. 3-6). In vitro experiments have suggested that CTCF mediates boundary activity of the maternal ICR, and that methylation of the paternal ICR abolishes this activity by preventing CTCF binding. Using mice with point mutations in all four CTCF sites in the ICR, we show that maternally transmitted mutant ICRs in neonatal mice acquire a substantial but heterogeneous degree of methylation. Mutant ICRs in oocytes and blastocysts are not methylated, however, indicating that binding of CTCF is not required to establish the unmethylated ICR during oogenesis. We also show that the mutant ICR lacks enhancer-blocking activity, as the expression of Igf2 is activated on mutant maternal chromosomes. Conversely, maternal H19 expression is reduced, suggesting a positive role for CTCF in the transcription of that gene. This study constitutes the first in vivo demonstration of the multiple functions of CTCF in an ICR.
Expression of the X-inactivation-associated gene XIST during spermatogenesis.
Mammalian X-chromosome inactivation is thought to be controlled by the X inactivation centre (XIC, X-controlling element -Xce-in mice). A human gene, XIST and its mouse counterpart, Xist, which map to the XIC/Xce, are expressed exclusively from inactive X chromosomes, suggesting their involvement in the process of X-inactivation. We now report the presence of Xist/XIST transcripts in newborn and adult mouse testes, and in human testicular tissue with normal spermatogenesis, but not in the testes of patients who lack germ cells. Our results indicate that while the X chromosome in males is active in somatic cells, it undergoes inactivation during spermatogenesis.
Expression of Xist in mouse germ cells correlates with X-chromosome inactivation.
Mammals compensate for different doses of X-chromosome-linked genes in male (XY) and female (XX) somatic cells by terminally inactivating all but one X chromosome in each cell. A transiently inactive X chromosome is also found in germ cells, specifically in premeiotic oogenic cells and in meiotic and postmeiotic spermatogenic cells. Here we show that the Xist gene, which is a expressed predominantly from the inactive X-chromosome in female somatic cells, is also expressed in germ cells of both sexes, but only at those stages when an inactive X chromosome is present. This suggests support for the putative role of Xist as a regulator of X-chromosome inactivation and suggest a common mechanism for the initiation and/or maintenance of X-chromosome inactivation in all cell types.
A chromatin model of IGF2/H19 imprinting.
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The pre-implantation ontogeny of the H19 methylation imprint.
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A promoter mutation in the XIST gene in two unrelated families with skewed X-chromosome inactivation.
X-chromosome inactivation is the process by which a cell recognizes the presence of two copies of an X chromosome early in the development of XX embryos and chooses one to be active and one to be inactive. Although it is commonly believed that the initiation of X inactivation is random, with an equal probability (50:50) that either X chromosome will be the inactive X in a given cell, significant variation in the proportion of cells with either X inactive is observed both in mice heterozygous for alleles at the Xce locus and among normal human females in the population. Families in which multiple females demonstrate extremely skewed inactivation patterns that are otherwise quite rare in the general population are thought to reflect possible genetic influences on the X-inactivation process. Here we report a rare cytosine to guanine mutation in the XIST minimal promoter that underlies both epigenetic and functional differences between the two X chromosomes in nine females from two unrelated families. All females demonstrate preferential inactivation of the X chromosome carrying the mutation, suggesting that there is an association between alterations in the regulation of XIST expression and X-chromosome inactivation.
Microdeletions in the human H19 DMR result in loss of IGF2 imprinting and Beckwith-Wiedemann syndrome.
The overgrowth- and tumor-associated Beckwith-Wiedemann syndrome results from dysregulation of imprinted genes on chromosome 11p15.5. Here we show that inherited microdeletions in the H19 differentially methylated region (DMR) that abolish two CTCF target sites cause this disease. Maternal transmission of the deletions results in hypermethylation of the H19 DMR, biallelic IGF2 expression, H19 silencing and Beckwith-Wiedemann syndrome, indicative of loss of function of the IGF2-H19 imprinting control element.