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PubMed2002

Allele-specific expression of imprinted genes in mouse migratory primordial germ cells.

In somatic cells, imprinted genes are expressed monoallelically according to parent-of-origin. In contrast, in 11.5 days post-coitum primordial germ cells (PGCs), and later stage germ cells, these same genes are expressed biallelically, suggesting that imprints inherited from the gametes are largely erased by this stage. To determine when in germ cell development this biallelic expression phenomenon commences, we isolated migrating PGCs by flow cytometry and determined the allele-specific expression of four imprinted genes - Snrpn, Igf2, H19 and Igf2r. The first three genes were expressed monoallelically, while the latter gene was expressed biallelically. These results show that inherited imprints regulating monoallelic expression are largely intact in migrating PGCs.

Alleles↗

PubMed1999

The genotype and epigenotype synergize to diversify the spatial pattern of expression of the imprinted H19 gene.

Little is known of how the genetic background effects the phenomenon of genomic imprinting. The H19 gene belongs to a cluster of imprinted genes on human chromosome 11. Here we show that the alternative splicing of a human H19 transcript is genotype-specific. Moreover, this variant transcript, which lacks exon 4, is either not found at all, is widely expressed or is confined to extra-villous cytotrophoblasts in first trimester placenta, depending on a combination of the genotype and the sex of the transmitting parent.

Alleles↗

PubMed2000

Embryonic inheritance of the chromatin organisation of the imprinted H19 domain in mouse spermatozoa.

Insulin-like growth factor 2 (Igf 2) and H19 genes are oppositely imprinted and as such have been most extensively studied imprinted genes both genetically and at the molecular level. Imprints of the H19 gene, being established during spermatogenesis, are epigenetically transmitted to the somatic cells of the embryo. Current hypotheses attempting to explain the allele-specific silence of the H19 gene include DNA methylation and chromatin condensation. In order to understand the molecular basis of H19 epigenesis, it is crucial to identify the markings in the chromatin organising the imprinted domain in spermatozoa. Using Micrococcal nuclease (MNase), DNase I and Methidiumpropyl-EDTA. iron II (MPE.Fe(II)) as chromatin probes, we demonstrate that in mouse epididymal spermatozoa, at least 4kb DNA upstream of the H19 'cap' site, containing the imprinted and differentially methylated domain (DMD), is heterochromatic. The cleavage sites in this domain (-2 to -4kb) exhibit approximately 425bp periodicity. This structure is maintained in the paternal allele of normal embryos and is disrupted at -2.2, -2.65 and at -3.5kb in embryos maternally disomic for the distal end of chromosome 7 (MatDp 7). The hypersensitive sites in chromatin precisely register the MPE.Fe(II) cleavage sites in chromosomal DNA. Therefore, the DNA sequences in the imprinted domain constrain the chromatin structure in a way similar to that of 1.688g/cm(3) Drosophila satellite chromatin. In addition, we find that condensation of the paternal allele correlates with methylation-dependent alteration in the structure of DNA sequences in DMD. These results suggest that CpG-methylation induces localised changes in DNA conformation and these facilitate consequent remodelling of chromatin thereby allowing the paternal and maternal H19 alleles to be distinguished.

Alleles↗

PubMed2000

Appropriate expression of the mouse H19 gene utilises three or more distinct enhancer regions spread over more than 130 kb.

H19 and Igf2 are closely linked, reciprocally imprinted genes which lie on distal chromosome 7 in the mouse. Data suggests that common elements are used for expression and imprinting of both genes, and simple models have been proposed based on the presence of a single set of enhancers located downstream of H19. In this study we have investigated the H19 expression pattern from a 130 kb YAC transgene, which imprints H19 appropriately at ectopic loci. However, we show that while enhancers for expression in many cell types are present on the YAC, those for expression in mesodermal components of the heart, kidney, lung and thymus are located at a greater distance. Based on the available evidence, we conclude that regulation of H19 is complex, requiring contribution from at least three different sets of cell-type specific enhancers. Thus, the mechanism of reciprocal imprinting of H19 and Igf2 utilises different regulatory elements in different cell types during mouse development.

Animals↗

PubMed2002

X-chromosome inactivation and the search for chromosome-wide silencers.

X-chromosome inactivation leads to divergent fates for two homologous chromosomes. Whether one X remains active or becomes silenced depends on the activity of Xist, a gene expressed only from the inactive X and whose RNA product 'paints' the X in cis. Recent work argues that Xist RNA itself is the acting agent for initiating the silencing step. Xist RNA contains separable domains for RNA localization and chromosome silencing. While no Xist RNA-interacting factors have been identified, a growing collection of chromatin alterations have been identified on the inactive X, including variant histone H2A composition and histone H3 methylation. Some or all of these changes may be critical for chromosome-wide silencing. As none of the silencing proteins identified so far is unique to X chromosome inactivation, the specificity must partly reside in Xist RNA whose spread along the X orchestrates general silencing factors for this specific task.

Animals↗

PubMed2003

Dosage compensation: an intertwined world of RNA and chromatin remodelling.

Dosage compensation mechanisms in flies and mammals provide an exquisite example of chromatin associated RNAs in chromosome-wide transcription regulation. Recent progress shows that chromatin modifications are also closely linked to these processes. Concerted action of the RNA/chromatin-modifying enzymes may play a crucial role in determining transcriptional output. Furthermore, non-coding RNAs appear to play a dual role, being targeting modules as well as encoding for target sites for complex recognition.

Animals↗

PubMed1994

X chromosome inactivation and the Xist gene.

X chromosome inactivation in mammals was first described over 30 years ago. The biological problem is how to achieve gene dosage equivalence between XX females and XY males; the solution is to genetically silence one whole X chromosome in each cell of the early developing female embryo. The molecular mechanism by which this is achieved, however, remains a mystery. Recently, through the discovery of the Xist gene, it appears that we may be on the brink of learning how this unique phenomenon is mediated. Here, I discuss the developmental regulation of X inactivation and the candidacy of Xist as the X chromosome inactivation centre, with particular reference to its possible role in the initiation, spread and maintenance of X inactivation.

Animals↗

PubMed1997

The (epi)genetic control of mammalian X-chromosome inactivation.

In mammals, the X chromosome is uniquely capable of complete inactivation. Research in the past two years has validated the long-held hypothesis that the 'X-inactivation center' (Xic) controls events of X inactivation and that its resident gene Xist is not only required but is at least partially responsible for the cis-restriction of X inactivation. Progress has also been made in identifying genes within the Xic. Although Xist remains the only known required element, evidence now suggests that a separate element for X counting must exist and that the Xic may be entirely contained within a 450 kb sequence. This small region may be sufficient for both initiation and establishment of X inactivation.

Animals↗

PubMed1998

The role of Xist in X-inactivation.

The past year has seen important progress in our understanding of the role of the X inactive specific transcript gene (Xist) in the initiation and propagation of X-inactivation. A 35 kb Xist transgene had been shown to recapitulate the functions of the X-inactivation centre, progress has been made towards indentifying factors controlling the randomness of X-inactivation, and RNA stabilisation has been shown to play a role in Xist regulation at the onset of X-inactivation.

Animals↗

PubMed1999

Mechanisms of genomic imprinting.

A small number of mammalian genes undergo the process of genomic imprinting whereby the expression level of the alleles of a gene depends upon their parental origin. In the past year, attention has focused on the mechanisms that determine parental-specific expression patterns. Many imprinted genes are located in conserved clusters and, although it is apparent that imprinting of adjacent genes is jointly regulated, multiple mechanisms among and within clusters may operate. Recent developments have also refined the timing of the gametic imprints and further defined the mechanism by which DNA methyltransferases confer allelic methylation patterns.

Alleles↗

PubMed2000

Genomic imprinting of IGF2 and H19 in human meningiomas.

A number of genes, including IGF2 and H19, are normally imprinted with preferential expression of the paternal or maternal allele, respectively. Loss of imprinting (LOI) of IGF2 and H19 is found in a number of tumours, suggesting that LOI of IGF2 and/or H19 may play an important role in tumorigenesis. The IGF2 gene codes for a fetal growth factor and the H19 gene is likely to act as an RNA with an antitumour effect. We investigated the imprinting status of IGF2 and H19 in human meningiomas. The normally imprinted IGF2 gene lacks imprint in the leptomeninges and choroid plexus of the brain. To examine the imprinting status of IGF2 and H19 in human meningiomas we used the ApaI polymorphism in exon 9 for the IGF2 gene and the AluI polymorphism in exon 5 for the H19 gene. In total, 24 meningiomas of WHO grade I, II and III were analysed. 15 meningiomas (63%) were informative for the ApaI polymorphism in the IGF2 gene. Monoallelic expression (MAE) for IGF2 was found in 11 out of 15 tumours (73%) which is in contrast to the lack of imprinting status of IGF2 in leptomeninges. Ten cases (42%) were heterozygous for the H19 gene and biallelic expression was found in 3 out of 10 meningiomas (30%). These results indicate that modulation of the imprinting status of IGF2 and H19 may play an important role for the development of meningiomas.

Adolescent↗

PubMed2003

Ligand-independent coactivation of ERalpha AF-1 by steroid receptor RNA activator (SRA) via MAPK activation.

Nuclear receptor coactivators are factors that enhance the transcriptional activity of the receptor. Coactivators usually work in ligand-independent and/or dependent manners by interacting with activation function-1 (AF-1) and AF-2 of the receptor, respectively. The recently characterized steroid receptor RNA activator (SRA) was cloned as an AF-1-dependent coactivator and shown to enhance the transcriptional activity of selected steroid receptors. In this work, we describe the effect of SRA on the activity of the two estrogen receptor (ER) isoforms, ERalpha and ERbeta. We show that SRA potentiates the estrogen-induced transcriptional activity of both ERalpha and ERbeta. We demonstrate that the transcriptional activity of ERalpha can be enhanced by SRA in a ligand-independent manner through the AF-1 domain. However, this AF-1-dependent effect of SRA is not observed on ERbeta, denoting the ability of SRA to mediate differential activation of ERalpha and ERbeta. The presence of an intact serine residue at position 118 (S(118)) in ERalpha AF-1 is required for coactivation of ERalpha by SRA. We also show that activation of the mitogen activated protein kinase (MAPK) induces ligand-independent coactivation of ERalpha by SRA, a mechanism that is independent of the AF-2. Finally, SRA is unable to rescue the loss of activity of the S(118) ERalpha mutant in response to H-Ras(V12), suggesting that phosphorylation of S(118) by MAPK participates in the ligand-independent effect of SRA on ERalpha.

Animals↗

PubMed2000

The 5' flank of mouse H19 in an unusual chromatin conformation unidirectionally blocks enhancer-promoter communication.

BACKGROUND: During mouse prenatal development, the neighbouring insulin-like growth factor II (Igf2) and H19 loci are expressed monoallelically from the paternal and maternal alleles, respectively. Identical spatiotemporal expression patterns and enhancer deletion experiments show that the Igf2 and H19 genes share a common set of enhancers. Deletion of a differentially methylated region in the 5' flank of the H19 gene partially relieves the repression of the maternal Igf2 and paternal H19 alleles in the soma. The mechanisms underlying the function of the 5' flank of the H19 gene are, however, unknown. RESULTS: Chromatin analysis showed that the 5' flank of the mouse H19 gene contains maternal-specific, multiple nuclease hypersensitive sites that map to linker regions between positioned nucleosomes. These features could be recapitulated in an episomal-based H19 minigene, which was propagated in human somatic cells. Although the 5' flank of the H19 promoter has no intrinsic silencer activity under these conditions, it unidirectionally extinguished promoter-enhancer communications in a position-dependent manner, without directly affecting the enhancer function. CONCLUSIONS: The unmethylated 5' flank of the H19 gene adopts an unusual and maternal-specific chromatin conformation in somatic cells and regulates enhancer-promoter communications, thereby providing an explanation for its role in manifesting the repressed state of the maternally inherited Igf2 allele.

Alleles↗

PubMed2000

Maternal-specific footprints at putative CTCF sites in the H19 imprinting control region give evidence for insulator function.

Parent-of-origin-specific expression of the mouse insulin-like growth factor 2 (Igf2) gene and the closely linked H19 gene are regulated by an intervening 2 kb imprinting control region (ICR), which displays parentspecific differential DNA methylation [1] [2]. Four 21 bp repeats are embedded within the ICR and are conserved in the putative ICR of human and rat Igf2 and H19, suggesting that the repeats have a function [3] [4]. Here, we report that prominent DNA footprints were found in vivo on the unmethylated maternal ICR at all four 21 bp repeats, demonstrating the presence of protein binding. The methylated paternal ICR displayed no footprints. Significantly, the maternal-specific footprints were localized to putative binding sites for CTCF, a highly conserved zinc-finger DNA-binding protein with multiple roles in gene regulation including that of chromatin insulator function [5] [6]. These results strongly suggest that the maternal ICR functions as an insulator element in regulating mutually exclusive expression of Igf2 and H19 in cis.

Animals↗

PubMed2000

Transcriptional control: imprinting insulation.

Recent studies on the transcriptional regulation of two linked, imprinted genes, Igf2 and H19, have provided evidence for a novel mechanism of epigenetic control. DNA methylation controls the activity of an insulator element located between the two linked genes by regulating the binding of the zinc-finger protein CTCF.

Animals↗

PubMed2000

Functional association of CTCF with the insulator upstream of the H19 gene is parent of origin-specific and methylation-sensitive.

In mammals, a subset of genes inherit gametic marks that establish parent of origin-dependent expression patterns in the soma ([1] and references therein). The currently most extensively studied examples of this phenomenon, termed genomic imprinting, are the physically linked Igf2 (insulin-like growth factor II) and H19 genes, which are expressed mono-allelically from opposite parental alleles [1] [2]. The repressed status of the maternal Igf2 allele is due to cis elements that prevent the H19 enhancers [3] from accessing the Igf2 promoters on the maternal chromosome [4] [5]. A differentially methylated domain (DMD) in the 5' flank of H19 is maintained paternally methylated and maternally unmethylated [6] [7]. We show here by gel-shift and chromatin immunopurification analyses that binding of the highly conserved multivalent factor CTCF ([8] [9] and references therein) to the H19 DMD is methylation-sensitive and parent of origin-dependent. Selectively mutating CTCF-contacting nucleotides, which were identified by methylation interference within the extended binding sites initially revealed by nuclease footprinting, abrogated the H19 DMD enhancer-blocking property. These observations suggest that molecular mechanisms of genomic imprinting may use an unusual ability of CTCF to interact with a diverse spectrum of variant target sites, some of which include CpGs that are responsible for methylation-sensitive CTCF binding in vitro and in vivo.

Animals↗

PubMed2000

Genetic imprinting: silencing elements have their say.

Tissue-specific silencing elements have been identified that are required for imprinting of the individual genes in the Igf2-H19 domain of the mouse genome. These elements further elaborate the differences between the two parental chromosomes, and add a new feature to parent-of-origin-specific gene regulatory complexes.

Animals↗

PubMed2000

Higher concentrations of histone macroH2A in the Barr body are correlated with higher nucleosome density.

Histone macroH2A, which is a subtype of histone H2A, possesses a histone H2A-like portion fused to a relatively long non-histone portion. MacroH2A has been shown to associate preferentially with the inactive X chromosome [1]. To investigate the specificity of this association, the nuclear distribution of macroH2A was compared with that of regular core histones. In normal human female fibroblasts, all anti-histone antibodies that were tested (including anti-macroH2A antibody) preferentially labeled the inactive X chromosome. Moreover, when expressed as green fluorescent protein (GFP) fusions, both histone H2A and macroH2A were concentrated in the Barr body. These data clearly show the presence of a higher density of nucleosomes in the inactive X chromosome. Accordingly, the specificity of the macroH2A association with the inactive X chromosome should be reconsidered. While investigating the role of macroH2A, we found that the proximity of the non-histone region of macroH2A to a promoter could lead to a specific repression of transcription, suggesting that the incorporation of macroH2A into chromatin might help to establish the stable pattern of gene expression in differentiated cells.

Female↗