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PubMed2001

Epigenetic mark sequence of the H19 gene in human sperm.

We have investigated the epigenetic mark in the human H19 gene. The H19 promoter is methylation-free in human sperm, but it is methylated in the paternally derived allele of most adult tissues. Consequently, the H19 gene is exclusively transcribed from the maternal allele. It was demonstrated that the differentially methylated region (DMR) located 2 kb upstream from mouse H19 is essential for the imprinting of H19. A 39 bp sequence in DMR has a high degree of similarity between humans, mice and rats. The highly conserved 15 bp core region of the consensus sequence contains four methylatable sites, and thus has been proposed as a potential imprinting mark region. In this study, fine epigenetic sequencing analysis was performed on the sperm DNA in comparison with other adult organs. Interestingly, the conserved sequence of the potential mark region was methylated in almost all the sperm genomes analyzed. Furthermore, the single dinucleotide CpG, whose methylation affects the accessibility of the element to CTCF, was methylated in the conserved core in the human sperm. These results suggest that the human core sequences may act as an imprinting center in the reciprocal monoallelic expression of H19.

Adult↗
PubMed2003

H19 and Igf2--enhancing the confusion?

Genomic imprinting, whereby certain genes are expressed dependent on whether they are maternally or paternally inherited, is restricted to mammals and angiosperm plants. This unusual mode of gene regulation results from the complex interplay between cis-regulatory elements, leading to parent-of-origin-dependent epigenetic modifications and tissue-specific patterns of imprinted gene expression. Many studies of imprinting and imprinted genes have focused on epigenetic effects, such as DNA methylation and chromatin structure. However, it is equally important to explore the interconnected role of regulatory elements at imprinted domains by genetic experiments, including the use of transgenes and deletions.

Animals↗
PubMed2002

X-chromosome inactivation: closing in on proteins that bind Xist RNA.

X inactivation is the developmentally regulated silencing of a single X chromosome in XX female mammals. In recent years, the Xist gene has been revealed as the master regulatory switch controlling this process. Parental imprinting and/or counting mechanisms ensure that Xist is expressed only on the inactive X chromosome. Chromosome silencing then results from the accumulation of the Xist RNA silencing signal, in cis, over the entire length of the X chromosome. A key issue has been to identify the factors that interact with Xist RNA to initiate heritable gene silencing. This review discusses recent progress that has put this goal in sight.

Animals↗
PubMed1997

DNA methylation and imprinting: why bother?

DNA methylation is crucial for mammalian development because embryos that cannot maintain normal methylation levels die after gastrulation. I propose that DNA methylation is only important for the somatic lineages, but has no role in embryonic lineages including the germ line. Among vertebrates, genomic imprinting is found only in mammals, and numerous hypotheses have ascribed an essential function to imprinting because of the uniquely mammalian developmental and physiological requirements. However, our understanding of molecular details of the imprinting process, as well as evolutionary considerations, is rather consistent with imprinting having no intrinsic role in mammalian development.

Animals↗
PubMed1997

Imprinting in clusters: lessons from Beckwith-Wiedemann syndrome.

Imprinted genes in mammals can be clustered in the genome. This raises important questions about mechanistic and functional relationships between imprinted genes in a cluster. The insulin-like growth factor II (IGF2) gene is paternally expressed and is surrounded by maternally expressed genes. Loss of imprinting of IGF2 is the most common molecular defect found in the human foetal overgrowth syndrome, Beckwith-Wiedemann syndrome (BWS). Transgenic experiments in the mouse establish that overexpression of IGF2 can result in most of the symptoms of BWS. However, mutations, translocations, or methylation defects in BWS have so far been found in three of the linked maternally expressed genes. We present a model where the paternal growth enhancer IGF2 is surrounded by multiple maternal suppressors, and mutations, or epigenetic alterations, in any of these suppressors could cause BWS. In addition, the precise phenotypic spectrum of BWS might depend on which maternally expressed gene is mutated.

Animals↗
PubMed1999

Isolation of sex-specific cDNAs from fetal mouse brain using mRNA differential display and representational difference analysis.

Comparing female and male brain structures reveals a variety of sex differences in many vertebrates. These differences are manifested throughout the brain, in regions such as the hypothalamus, the preoptic area and the amygdala. Some are thought to be induced during the fetal period by the effect of steroid hormones produced in the gonads. It is well-established that fetal androgens, probably through the conversion to estrogen by the enzyme aromatase, masculinize the nervous system and set adult mounting behavior in rodents. However, less is known about molecular mechanisms involved in gender-specific development of the brain. We have taken a broad approach to isolate sex-specific genes from fetal brain. mRNAs from 18.5 days post-coitum (dpc) female and male mouse brain were screened with the classical and the recently developed signal peptide differential display (SPDD) and with representational difference analysis of cDNA (cDNA-RDA). Two sex-specific cDNAs were isolated, F29 and M17, corresponding to the female-specific Xist gene and the male-specific Smcy gene, respectively.

Amino Acid Sequence↗
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↗
PubMed2001

Sequence analysis of the MHC class I region reveals the basis of the genomic matching technique.

The genomic matching technique (GMT) improves survival following bone marrow transplantation (BMT) between unrelated donor and recipient pairs correlating with a decrease in incidence and severity of graft-versus-host disease (GvHD). The principles of this technique are based on the duplication and polymorphic characteristics of the major histocompatibility complex (MHC). Specifically, the beta block GMT matches for a 300 kb region that contains the human leukocyte antigen (HLA-B and -C) genes as well as other non-HLA genes such as the natural killer cell receptor ligand PERB11 (MIC). The block contains two large segmental duplications. One results in two PERB11 genes (11.1 and 11.2), the other in two class I genes (HLA-B and -C). With the complete sequencing of the class I region of the MHC in different haplotypes, we can now show that the beta block GMT profiles reflect amplification of the duplicated PERB11 segments and not the duplicated segments containing HLA-B and -C, and yet provide a signature that characterizes the entire block rather than individual loci.

Base Sequence↗
PubMed1999

Expression of the imprinted H19 oncofetal RNA in epithelial ovarian cancer.

STUDY: To examine the expression of the imprinted maternally expressed H19 gene in benign, low malignant potential (borderline) and malignant surface epithelial ovarian tumors. DESIGN: In situ hybridization for H19 RNA using S-labeled and digoxigenin-labeled probes was performed on paraffin sections of ovarian surface epithelial tumors. The serous tumors included nine section cystadenomas, twelve serous tumors of low malignant potential and twenty serous carcinomas, grade I-IIII (FIGO classification). A smaller group included two mucinous cystadenomas, four mucinous tumors of low malignant potential and two mucinous cystadenocarcinomas. RESULTS: H19 expression was found to be positive in 6/9 (67%) serous cystadenomas, 9/12 (75%) of serous tumors of low malignant potential and 13/20 (65%) of invasive serous carcinomas. Expression in mucinous tumors was confined to the stroma beneath the epithelial lining. CONCLUSION: H19 is expressed in the majority of serous epithelial tumors. Taking into consideration the high percentage of H19 expressing serous ovarian neoplasms we suggest that H19 RNA may be used as an adjuvant tumor marker for the diagnosis and mainly for staging and follow-up of patients with serous ovarian carcinoma.

Adenocarcinoma↗
PubMed1997

Relaxation of insulin-like growth factor-2 imprinting in rat cultured cells.

The parental-specific expression of the insulin-like growth factor-2 (Igf-2) and H19 genes was studied in rat fibroblast cells derived from a 3 day-old first-generation hybrid animal obtained by crossing Fisher and Wistar strains (F x W cells). Results showed that the reciprocal imprinting of the Igf-2 and H19 genes was conserved in the rat tissues and in the derived F x W cells when cultured with frequent transfer. Igf-2 and H19 gene expression was coordinately up-regulated upon reaching confluence, but Igf-2 RNA levels were further increased in a time-dependent manner and the repressed state of the maternal Igf-2 allele was progressively relaxed in cultures held in the confluent state and in the presence of low serum for more than 3 days. The active expression and relaxed imprinting status of the Igf-2 gene persisted over cell generations when the growth-constraining conditions were released by trypsinization and dilution. On the contrary, the imprinting of the H19 gene appeared to be unaffected by changes in growth conditions and its expression was down-regulated when the confluent cells were passaged. Methylation of the H19 promoter and Igf-2 coding regions was increased in the F x W cells extensively held under confluence and in the derived 'post-confluent' cultures. The heritable changes in the expression, and imprinting status of the Igf-2 and H19 genes observed in the F x W cells closely resembles events described in human embryonal cancers and cancer-predisposing syndromes. The occurrence of imprinting relaxation under strong growth-inhibitory conditions supports the hypothesis that it is an epigenetic change.

Animals↗
PubMed1998

Xist and X chromosome inactivation.

X inactivation acts in female mammals to equalise X-linked gene dosage between XX females and XY males. X inactivation is controlled by a single X-linked cis-acting locus called the X inactivation centre (Xic). In 1991 the Xist gene was identified as a candidate for the Xic. Xist is expressed in all adult female tissues, but only from the allele on the inactive X. The Xist transcript does not encode a protein but remains sequestered within the nucleus and co-localises with the inactive X chromosome. Transgenic and knockout studies have shown that a genomic region covering only a few kilobases either side of Xist carries all of the functions attributed to the Xic. The major questions currently occupying researchers studying X inactivation are: how do cells count their number of X chromosomes to determine whether X inactivation is necessary, and how does the Xist transcript inactivate all genes on the X chromosome?

Dosage Compensation, Genetic↗
PubMed1997

Biallelic expression of the H19 and IGF2 genes in hepatocellular carcinoma.

The imprinted genes, H19 and insulin-like growth factor II (IGF2), have been demonstrated to be necessary for embryonal development in humans. Both genes are reciprocally imprinted, with expression of the maternal H19 and paternal IGF2 alleles, and are normally characterized by monoallelic expression. Recently, loss of imprinting of these genes producing biallelic expression has been observed in childhood tumors including Wilms' tumors (WT), embryonal rhabdomyosarcoma, and adulthood tumors such as lung cancer. To test the existence of loss of imprinting in hepatocellular carcinoma (HCC), we analyzed the status of imprinting of H19 and IGF2 genes in three independent tumors, three HCC and one hepatoblastoma cell lines using AluI and ApaI polymorphisms of these genes, respectively. In contrast to the previous report, all the cases except one tumor and one HCC cell line showed biallelic expression of both H19 and IGF2 genes. Unlike WT, loss of imprinting (LOI) of IGF2 in HCC was not linked to down-regulation of H19 expression, but rather associated with coexpression for H19 and IGF2. Thus, Hl9 and IGF2 expression can be uncoupled in tumors with LOI. The frequent biallelic expression of H19 and IGF2 in hepatocellular carcinoma might play a causal role in the epigenetic mechanism involved in tumor development and/or process.

Carcinoma, Hepatocellular↗
PubMed1997

Loss of imprinting and overexpression of IGF2 gene in gastric adenocarcinoma.

Both insulin-like growth factor II (IGF2) and H19 gene are located on chromosome 11p15.5 in close vicinity to each other, and are imprinted on different parental alleles. Although the exact mechanism remains unclear, loss of imprinting (LOI) leading to the biallelic expression of IGF2 and H19 genes has recently been reported in a variety of tumors. To study the role of IGF2 and H19 genes in gastric carcinogenesis, the LOI and loss of heterozygosity (LOH) status of these two genes were determined in 70 patients with gastric cancer. Among them, 30 patients were heterozygous for IGF2, 28 patients were heterozygous for H19, and 42 patients were heterozygous for either IGF2 or H19 gene. Among the 30 patients who were heterozygous for IGF2, one exhibited LOH (1/30, 3.3%) and 10 exhibited LOI (10/29, 34.5%). None of the 28 patients heterozygous for H19 gene had either LOH or LOI. LOI of IGF2 was more frequently found in the diffuse type (8/15, 53.3%) than the intestinal type (2/14, 14.3%, P < 0.05) gastric cancer. Five out of the six tumors with LOI of IGF2 exhibited overexpression of mRNA, but no obvious alterations of expression of H19 were noted by Northern hybridization. These data suggest that LOI leading to overexpression of IGF2 plays an important role in carcinogenesis of diffuse type gastric cancer.

Adenocarcinoma↗