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At least 1,729 records · Page 96Linked to original sources
PubMed2004

Increased expression of H19 non-coding mRNA follows hepatocyte proliferation in the rat and mouse.

BACKGROUND/AIMS: H19 is a paternally imprinted gene that is believed to function as non-coding mRNA. While H19 is only faintly expressed in the normal adult liver, it is abundantly expressed during the fetal period. We explored the possibility that H19 might participate in the regulation of hepatocyte proliferation. METHODS: Adult male rats and mice were subjected to a two-thirds partial hepatectomy, and after various time periods, hepatocytes were isolated and analyzed for H19 gene expression. The expression was also examined in cultured rat hepatocytes. RESULTS: The expression of H19 was dramatically increased after 2 days (rat) and 4 days (mouse), peaked at 3 days (rat) and 6 days (mouse), and then gradually declined. In both species, the increase in H19 gene expression was preceded by the induction of proliferating cell nuclear antigen and DNA synthesis. An allele-specific RT-PCR analysis in the mouse showed that the paternally imprinted status of the gene was maintained after a partial hepatectomy. H19 was strongly induced in spheroid cultures after transient hepatocyte proliferation, but not in conventional monolayer cultures, in which persistent proliferation occurred. CONCLUSIONS: Our results demonstrated that H19 gene expression was dynamically regulated in adult hepatocytes in close association with their proliferation.

Animals↗
PubMed2005

Expression pattern of the maternally imprinted gene Gtl2 in the forebrain during embryonic development and adulthood.

Recent work has uncovered a large number of imprinted genes, many of which are thought to play a role in neurodevelopment and behavior. In order to begin to understand the role of specific genes in these processes, their expression patterns will be key. In this study we used in situ hybridization to study the developmental expression of Gtl2 in the forebrain from E12.5 to adulthood, since preliminary data from a microarray study indicated differential expression between the ventral and dorsal telencephalon of the mouse at a critical time point in the generation and migration of cortical neuronal populations. Strong expression was observed in the diencephalon, ventral telencephalon, post mitotic cell layers of the neocortex and pyramidal cell layer of the hippocampus. Additionally, heavily labeled subpopulations of laminar restricted cells were seen in the latter two areas.

Animals↗
PubMed2004

A 178-kb BAC transgene imprints the mouse Gtl2 gene and localizes tissue-specific regulatory elements.

The regulation of genomic imprinting, the allele-specific expression of an autosomal gene, is complex and poorly understood. Imprinted genes are organized in clusters, where cis-acting regulatory elements are believed to interact to control multiple genes. We have used BAC transgenesis in the mouse to begin to delineate the region of DNA required for proper expression and imprinting of the mouse Delta-like1 (Dlk1) and Gene-trap locus2 (Gtl2) imprinted genes. We demonstrate that the Gtl2 gene is expressed from a BAC transgene in mouse embryo and placenta only upon maternal inheritance, as is the endogenous Gtl2 gene. Gtl2 is therefore properly imprinted on the BAC in an ectopic chromosomal location and must carry with it all necessary imprinting regulatory elements. Furthermore, we show that the BAC Gtl2 gene is expressed at levels approaching those of the endogenous gene only in the brain of adult animals, not in other sites of endogenous expression such as the pituitary, adrenal, and skeletal muscle. These data localize the enhancer(s) for brain Gtl2 expression, but not those for other tissues, to the DNA contained within the BAC clone. As the Dlk1 gene is not expressed from the BAC in any tissues, it must require additional elements that are different from those necessary for Gtl2 expression. Our data refine the interval for future investigation of Gtl2 imprinting and provide evidence for distinct regulation of the linked Dlk1 and Gtl2 genes.

Animals↗
PubMed2007

A combined computational and experimental analysis of two families of snoRNA genes from Caenorhabditis elegans, revealing the expression and evolution pattern of snoRNAs in nematodes.

Small nucleolar RNAs (snoRNAs) are an abundant group of noncoding RNAs mainly involved in the posttranscriptional modifications of rRNAs in eukaryotes. Prior to this study, only 28 snoRNA genes had been identified from Caenorhabditis elegans, indicating that most snoRNA genes are hidden in the worm genome, which represents a simple multicellular metazoan. In this study, a genome-wide analysis of the two major families of snoRNA genes in C. elegans was performed using the snoscan and snoGPS programs incorporating comparative genome analyses. Seventy gene variants, including 36 box C/D and 34 box H/ACA snoRNA genes, were identified, of which 50 are novel. Two families of snoRNAs showed a characteristic genomic organization. Notably, 6 box C/D snoRNA genes were located in the antisense orientation of introns. In contrast to insect and mammal, the distances between many intronic snoRNAs and 3' splice sites of introns were less than 50 nt in the worm, an unexpected finding as intron-encoded snoRNAs in C. elegans are supposed to be expressed in a splicing-dependent pathway. Interestingly, a canonical H/ACA snoRNA, PsiCeU5-48, was revealed to be partially homologous to small Cajal body-specific RNA (scaRNA) U85 and U89 in fly and human, indicating a possible evolutionary relationship between snoRNAs and scaRNAs.

Animals↗
PubMedDate not supplied

DNA methylation, chromatin boundaries, and mechanisms of genomic imprinting.

In mammals, the maternal and paternal genomes are both required for normal embryonic and postnatal development. As a consequence, the majority of genes possess a bi-allelic pattern of expression, with the exception of certain loci where transcription is strictly dependent on parental origin. This alternative, termed genomic imprinting, is an epigenetic form of gene regulation that allows controlled expression of one parental allele. Experimental evidence supports the idea that chromatin organization, DNA methylation, replication timing, genomic domain organization, and more recently methylation-dependent boundary function are key components of imprinting mechanisms. Imprinted genes are mainly required during embryogenesis and development, but loss of controlled imprinting has direct consequences in carcinogenesis. For example, imprinted tumor suppressor genes and proto-oncogenes are highly susceptible to allelic inactivation or in contrast to activation that induces tumorigenic processes. Therefore, genomic imprinting represents one of the more challenging and interesting scientific and medical topics, and especially because a large combinatorial set of possibilities for gene regulation arises from the increasing number of imprinted loci identified.

Alleles↗
PubMed2000

CTCF mediates methylation-sensitive enhancer-blocking activity at the H19/Igf2 locus.

The Insulin-like growth factor 2 (Igf2) and H19 genes are imprinted, resulting in silencing of the maternal and paternal alleles, respectively. This event is dependent upon an imprinted-control region two kilobases upstream of H19 (refs 1, 2). On the paternal chromosome this element is methylated and required for the silencing of H19 (refs 2-4). On the maternal chromosome the region is unmethylated and required for silencing of the Igf2 gene 90 kilobases upstream. We have proposed that the unmethylated imprinted-control region acts as a chromatin boundary that blocks the interaction of Igf2 with enhancers that lie 3' of H19 (refs 5, 6). This enhancer-blocking activity would then be lost when the region was methylated, thereby allowing expression of Igf2 paternally. Here we show, using transgenic mice and tissue culture, that the unmethylated imprinted-control regions from mouse and human H19 exhibit enhancer-blocking activity. Furthermore, we show that CTCF, a zinc finger protein implicated in vertebrate boundary function, binds to several sites in the unmethylated imprinted-control region that are essential for enhancer blocking. Consistent with our model, CTCF binding is abolished by DNA methylation. This is the first example, to our knowledge, of a regulated chromatin boundary in vertebrates.

Animals↗
PubMed1998

Hypervariable allelic expression patterns of the imprinted IGF2 gene in tumor cells.

The IGF2 gene, which encodes a growth factor, is subject to genomic imprinting. The frequently observed loss of IGF2 imprinting in a variety of tumors has been suggested to contribute to neoplasia. Since these reports have not documented the imprinting status of IGF2 at the cellular level, it cannot be excluded that the imprinting status might vary within the tumor. The possibility that loss of IGF2 imprinting in neoplastic cells reflects random imprinting patterns, was therefore addressed. We show here that individual cell populations of the JEG-3 choriocarcinoma cell line display heterogenous imprinting patterns of both IGF2 and H19. In addition, a lack of correlation between IGF2 and H19 imprinting status suggests that any regional parental imprint has been functionally lost. This notion is reinforced by the observation that JEG-3 cell subclones display a range of promoter-specific IGF2 allele usage. Moreover, we observed that the imprinting status of H19 and IGF2 were differentially modulated in JEG-3-derived tumors generated in nude mice. The results suggest that allele-specific expression of IGF2 operates in the absence of a parental imprint. Finally, our observations urge caution with respect to the general interpretation of biallelic expression as 'loss of imprinting'.

Alleles↗
PubMed2006

Erasure of methylation imprint at the promoter and CTCF-binding site upstream of H19 in human testicular germ cell tumors of adolescents indicate their fetal germ cell origin.

Genome-wide epigenetic modification plays a crucial role in regulating genome functions at critical stages of development. In particular, DNA methylation is known to be reprogrammed on a genome-wide level in germ cells and in preimplantation embryos, although it is relatively stable in somatic cells. In this reprogramming process, the genome becomes demethylated, and methylated de novo during later stages of development. Reprogramming of DNA methylation in male germ cells has not been fully investigated. Testicular germ cell tumors (TGCTs) possess a pluripotential nature and display protean histology from germ cells to embryonal and somatic cell differentiation. These properties make TGCT a unique model for studying germ cell development and gametogenesis in respect of DNA reprogramming. In order to obtain an insight into the epigenetic dynamics of TGCTs, we conducted a comprehensive analysis of differential methylated regions (DMRs) on H19 and IGF2 in TGCTs compared with testicular malignant lymphomas. In the present study, we show that methylation imprint at the promoter and CTCF-binding site upstream of H19 was completely erased in both seiminomatous and non-seminomatous TGCTs, whereas differential methylation was observed in testicular lymphomas. The erasure of methylation imprint was also observed in TGCTs with malignant transformation. We found biallelic unmethylation at the promoter and the CTCF-binding site upstream of H19 is required, but not sufficient for the biallelic expression of H19 in TGCTs. These data suggest that factors other than methylation contribute to transcriptional regulation of imprinted genes in TGCTs. The present data have shown that TGCTs carry distinctive epigenetic profiles at the core-imprinting domain of H19/IGF2 from other neoplasms of somatic cell origin. The data also suggest that both seminomatous and non-seminomatous TGCTs carry methylation profiles similar to fetal germ cells, but not adult germ cells, indicating the origin of TGCTs as fetal germ cells.

Adolescent↗
PubMed2006

CTCF binding at the H19 imprinting control region mediates maternally inherited higher-order chromatin conformation to restrict enhancer access to Igf2.

It is thought that the H19 imprinting control region (ICR) directs the silencing of the maternally inherited Igf2 allele through a CTCF-dependent chromatin insulator. The ICR has been shown to interact physically with a silencer region in Igf2, differentially methylated region (DMR)1, but the role of CTCF in this chromatin loop and whether it restricts the physical access of distal enhancers to Igf2 is not known. We performed systematic chromosome conformation capture analyses in the Igf2/H19 region over >160 kb, identifying sequences that interact physically with the distal enhancers and the ICR. We found that, on the paternal chromosome, enhancers interact with the Igf2 promoters but that, on the maternal allele, this is prevented by CTCF binding within the H19 ICR. CTCF binding in the maternal ICR regulates its interaction with matrix attachment region (MAR)3 and DMR1 at Igf2, thus forming a tight loop around the maternal Igf2 locus, which may contribute to its silencing. Mutation of CTCF binding sites in the H19 ICR leads to loss of CTCF binding and de novo methylation of a CTCF target site within Igf2 DMR1, showing that CTCF can coordinate regional epigenetic marks. This systematic chromosome conformation capture analysis of an imprinting cluster reveals that CTCF has a critical role in the epigenetic regulation of higher-order chromatin structure and gene silencing over considerable distances in the genome.

Animals↗
PubMed1984

Intermediate filament cDNAs from BHK-21 cells: demonstration of distinct genes for desmin and vimentin in all vertebrate classes.

Recombinant cDNA plasmids for the intermediate filament proteins desmin and vimentin were constructed from baby hamster kidney (BHK-21) mRNA. Analysis of four desmin clones gave a sequence of 1574 nucleotides, which is 75% of the total mRNA length. The derived amino acid sequence for hamster desmin shows 92% overall homology with chicken desmin; the homology with hamster vimentin is highest in the alpha-helical middle part (74%). The 3'-noncoding region of desmin mRNA is found to be 677 nucleotides long. With the aid of 5'- and 3'-specific probes, it has been established that there is a single gene for desmin in the hamster genome. This gene expresses a single mRNA species of 2.2 kilobases. Hybridization experiments of a number of DNAs with desmin and vimentin probes show that there are distinct restriction enzyme fragments carrying vimentin and desmin sequences in the genome of representatives of all vertebrate classes.

Amino Acid Sequence↗
PubMed1993

Two functional soybean genes encoding p34cdc2 protein kinases are regulated by different plant developmental pathways.

We have isolated two cDNA clones (cdc2-S5 and cdc2-S6) encoding p34cdc2 protein kinases, homologs of yeast cdc2/CDC28 genes, from a soybean nodule cDNA library. The two sequences share 90% sequence homology in the coding regions. The 5' and 3' noncoding regions are distinct from each other, however, indicating that at least two genes encode p34cdc2 protein kinases in soybean. Both sequences can rescue the cdc28 mutation in Saccharomyces cerevisiae but rescue it with different efficiency. Genomic Southern analysis showed the existence of two copies for each of these genes, which are not closely linked and are nonallelic. The relative expression level of the two soybean p34cdc2 genes varies in different tissues. Expression of cdc2-S5 is higher in roots and root nodules, whereas cdc2-S6 is more actively expressed in aerial tissues, indicating that regulation of these two p34cdc2 genes is coupled with plant developmental pathways. Expression of cdc2-S5 is, furthermore, enhanced after Rhizobium infection, whereas cdc2-S6 fails to respond, suggesting that cdc2-S5 plays a role in nodule initiation and organogenesis. This latter gene preferentially responds to auxin (alpha-naphthaleneacetic acid) treatment, indicating that phytohormones may be involved in the control of cell division mediated by Rhizobium infection. Thus, different p34cdc2 protein kinases may control cell division in different tissues in a multicellular organism and respond to different signals--e.g., phytohormones.

Amino Acid Sequence↗
PubMed1984

Polymorphic sites and the mechanism of evolution in human mitochondrial DNA.

Twelve restriction enzymes were used to screen for the presence or absence of cleavage sites at 441 locations in the mitochondrial DNA of 112 humans from four continents. Cleavage maps were constructed by comparison of DNA fragment sizes with those expected from the published sequence for one human mtDNA. One hundred and sixty-three of the sites were polymorphic, i.e., present in some individuals but absent from others, 278 sites being invariant. These polymorphisms probably result from single base substitutions and occur in all functional regions of the genome.--In 77 cases, it was possible to specify the exact nature and location (within a restriction site) of the mutation responsible for the absence of a restriction site in a known human mtDNA sequence and its presence in another human mtDNA. Fifty-two of these 77 gain mutations occur in genes coding for proteins, 34 being silent and 18 causing amino acid replacements; moreover, nine of the replacements are radical.--Notable also is the anomalous ratio of transitions to transversions required to account for these 77 restriction site differences between the known human mtDNA sequences and other human mtDNAs. This ratio is lower for most groups of restriction sites than has been reported from sequence comparisons of limited parts of the mtDNA genome in closely related mammals, perhaps indicating a special functional role or sensitivity to mutagenesis for palindromic regions containing high levels of guanine and cytosine.--From the genomic distribution of the 163 polymorphic sites, it is inferred that the level of point mutational variability in tRNA and rRNA genes is nearly as high as in protein-coding genes but lower than in noncoding mtDNA. Thus, the functional constraints operating on components of the protein-synthetic apparatus may be lower for mitochondria than for other systems. Furthermore, the mitochondrial genes for tRNAs that recognize four codons are more variable than those recognizing only two codons.--Among the more variable of the human mitochondrial genes coding for proteins is that for subunit 2 of cytochrome oxidase; this polypeptide appears to have been evolving about five times faster in primates than in other mammals. Cytochrome c, a nuclearly encoded protein that interacts directly with the oxidase 2 subunit in electron transport, has also evolved faster in primates than in rodents or ungulates. This example, along with that for the mitochondrial rRNA genes and the nuclear genes coding for mitochondrial ribosomal proteins, provides evidence for coevolution between specific nuclear and mitochondrial genes.

Base Sequence↗
PubMed2002

An evolutionarily conserved putative insulator element near the 3' boundary of the imprinted Igf2/H19 domain.

Igf2 and H19 are closely linked imprinted genes lying at the centromeric end of a 1 Mb imprinted domain on mouse chromosome 7. L23mrp and other genes located 3' (more centromeric) to H19 are not imprinted and do not interact with the enhancers shared by Igf2 and H19. It is therefore suggested that the intergenic region between H19 and L23mrp contains a boundary or an insulator element. We have identified a binding site for CTCF, a nuclear factor that mediates insulator activity in vertebrates, in the intergenic region. This site is conserved between human and mouse, associated with a major DNase I-hypersensitive site, and bound by CTCF in vivo. Functional assays using reporter constructs demonstrated that this element functions as an insulator in transfected cells. The findings suggest that this CTCF site contributes to the 3' boundary of this imprinted domain. Together with the findings on the differentially methylated CTCF sites 5' to H19, CTCF-dependent insulators may not only regulate but also delimit the imprinted domain.

3' Flanking Region↗
PubMed1995

Imprinting mutations in the Beckwith-Wiedemann syndrome suggested by altered imprinting pattern in the IGF2-H19 domain.

Regional regulations of parental imprinting in the IGF2-H19 domain of imprinted genes was studied in the Beckwith-Wiedemann syndrome (BWS). We identified BWS patients who had inherited a normal biparental chromosome complement of the chromosome 11p15.5 region (where IGF2 and H19 reside), but had an altered pattern of allelic methylation of both genes, with the maternal chromosome carrying a parental imprinting pattern. In fibroblasts, IGF2 was expressed from both parental alleles and H19 was not expressed, precisely as predicted from the altered pattern of allelic methylation. Interestingly, DNA replication patterns of the 11p15.5 region remained asynchronous as in controls. Our results therefore provide the first example of the dissociation of regional control of DNA replication from regional control of allelic methylation and expression in imprinting. We suggest that the altered pattern of allelic methylation and expression arises in the germline or in the early embryo from defects in resetting or setting of imprinting in maternal germline. Potential candidate regions for mutations include the previously identified translocation breakpoint clusters and the H19 gene itself. The finding of possible 'imprinting mutations' in BWS raises the prospect of identifying genetic factors that control imprinting in this region.

Base Sequence↗
PubMed1999

Multipoint analysis of human chromosome 11p15/mouse distal chromosome 7: inclusion of H19/IGF2 in the minimal WT2 region, gene specificity of H19 silencing in Wilms' tumorigenesis and methylation hyper-dependence of H19 imprinting.

WT2 is defined by maternal-specific loss of heterozygosity (LOH) on chromosome 11p15.5 in Wilms' tumors (WTs). The imprinted H19 gene, in this region, is silenced and hypermethylated in most WTs, and this is linked to pathological biallelic expression of IGF2. However, H19 and IGF2 lie within a larger imprinted domain, and the gene specificity of H19 epimutation has been a persistent question. To address this, we assessed LOH, gene expression and DNA methylation at multiple sites in and around the imprinted domain. LOH mapping showed that the entire domain, including IGF2/H19, is within the minimal WT2 region. Genes within the domain, including IPL/TSSC3/BWR1C, IMPT1/ORCTL2/BWR1A/TSSC5, KvLQT1/KCNA9 and TAPA1/CD81, as well as the zinc finger gene ZNF195/ZNFP104 near the centromeric border, were expressed persistently in many WTs. DNA hypermethylation was not detected with 5" upstream probes for IPL, IMPT1, KvLQT1 and ZNF195 in WTs or WT-associated kidneys. Fully developed WTs showed variable hypomethylation at an imprinted CpG island in a KvLQT1 intron, but this was only complete in the cases with LOH and was not observed in pre-neoplastic WT-associated kidneys with H19 epimutation. Analysis of the corresponding region of mouse chromosome 7 using methyltransferase-hypomorphic mice showed that the H19 imprint was fully erased, but that the allelic bias at Ipl, Impt1, p57 Kip2 and, to a lesser extent, Kvlqt1, persisted. Pre-existing massive allelic asymmetry for DNA methylation and hyper-dependence of transcription on methylation status may underlie the mechanism of gene-specific silencing of H19 in Wilms' tumorigenesis.

Animals↗
PubMed2006

CTCF binding sites promote transcription initiation and prevent DNA methylation on the maternal allele at the imprinted H19/Igf2 locus.

Imprinting at the H19/Igf2 locus depends on a differentially methylated domain (DMD) acting as a maternal-specific, methylation-sensitive insulator and a paternal-specific locus of hypermethylation. Four repeats in the DMD bind CTCF on the maternal allele and have been proposed to recruit methylation on the paternal allele. We deleted the four repeats and assayed the effects of the mutation at the endogenous locus. The H19DMD-DeltaR allele can successfully acquire methylation during spermatogenesis and silence paternal H19, indicating that these paternal-specific functions are independent of the CTCF binding sites. Maternal inheritance of the mutations leads to biallelic Igf2 expression, consistent with the loss of a functional insulator. Additionally, we uncovered two previously undescribed roles for the CTCF binding sites. On the mutant allele, H19 RNA is barely detectable in 6.5 d.p.c. embryos and 9.5 d.p.c. placenta, for the first time identifying the repeats as the elements responsible for initiating H19 transcription. Furthermore, methylation is abruptly acquired on the mutant maternal allele after implantation, a time when the embryo is undergoing genome-wide de novo methylation. Together, these experiments show that in addition to being essential for a functional insulator, the CTCF repeats facilitate initiation of H19 expression in the early embryo and are required to maintain the hypomethylated state of the entire DMD.

Alleles↗
PubMed1986

Analysis of the genome structure of tobacco rattle virus strain PSG.

The sequence of the 3'-terminal 2077 nucleotides of genomic RNA 1 and the complete sequence of genomic RNA 2 of tobacco rattle virus (TRV, strain PSG) has been deduced. RNA 2 (1905 nucleotides) contains a single open reading frame for the viral coat protein (209 amino acids), flanked by 5'- and 3'-noncoding regions of 570 and 708 nucleotides, respectively. A subgenomic RNA (RNA 4) was found to lack the 5'-terminal 474 nucleotides of RNA 2 and is the putative messenger for coat protein. The deduced RNA 1 sequence contains the 3'-terminal part of a reading frame that probably corresponds to the TRV 170K protein and reading frames for a 29K protein and a 16K protein. Proteins encoded by the first two reading frames show significant amino acid sequence homology with corresponding proteins encoded by tobacco mosaic virus. Subgenomic RNAs 3 (1.6 kb) and 5 (0.7 kb) were identified as the putative messengers for the 29K and 16K proteins, respectively. At their 3'-termini all PSG-RNAs have an identical sequence of 497 nucleotides; at the 5'-termini homology is limited to 5 to 10 bases.

Amino Acid Sequence↗
PubMed2004

Exposure of mouse preimplantation embryos to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alters the methylation status of imprinted genes H19 and Igf2.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an extremely toxic, persistent environmental contaminant that disrupts normal development in laboratory animals. In our earlier study, we found that exposure of preimplantation embryos to TCDD markedly induced cytochrome P4501A1 mRNA at the blastocyst stage. In the present study, to determine whether exposure of preimplantation embryos to TCDD affects fetal growth, we exposed preimplantation embryos to TCDD from the 1-cell stage to the blastocyst stage and then transferred them to unexposed recipient mice. On Embryonic Day 14, the fetuses exposed to TCDD during the preimplantation stage weighed less than the fetuses in the unexposed control group. Real-time reverse transcription-polymerase chain reaction analysis revealed that exposure of preimplantation embryos to TCDD tended to decrease the expression levels of the imprinted genes H19 and Igf2 (insulin-like growth factor 2 gene). Use of bisulfite genomic sequencing demonstrated that the methylation level of the 430- base pair H19/Igf2 imprint control region was higher in TCDD- exposed embryos and fetuses than in the controls, and methyltransferase activity was also higher in the TCDD-exposed embryos than in the controls. To our knowledge, the present study is the first to provide evidence that TCDD exposure at the preimplantation stage alters the genomic DNA methylation status of imprinted genes, influences the expression level of imprinted genes, and affects fetal development.

Animals↗