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PubMedDate not supplied

H19 and IGF2 gene expression in human normal, hyperplastic, and malignant endometrium.

We examined H19 and insulin-like growth factor 2 (IGF2) gene expression in normal endometrium (12 cases), hyperplasia (27 cases), and cancer (27 cases) by non-radioactive in situ hybridization. H19 was not expressed in the epithelium of normal endometrium, but its frequency of expression was 15% in hyperplastic and 60% in neoplastic epithelium. In stroma cells, H19 frequency of expression was 75% in normal endometrium, 55% in hyperplasia, and 37% in carcinoma. According to the grade of endometrial cancer cell differentiation, H19 showed increased frequency and level of expression in the epithelium from well to moderately and poorly differentiated tissues. Our results indicate that H19 expression in epithelial cells of endometrial hyperplasia and cancer merits further investigation and could be useful as a complementary histopathologic and prognostic marker among other modalities in endometrial cancer. IGF2 expression did not appear useful for diagnostic or prognostic purposes.

Case-Control Studies↗
PubMed1996

Equivalent parental distribution of frequently lost alleles and biallelic expression of the H19 gene in human testicular germ cell tumors.

Epigenetic alterations such as genomic imprinting might play an important role in human tumorigenesis, in addition to specific genetic alterations. To clarify the role of genetic and/or epigenetic alterations in the tumorigenesis of testicular germ cell tumors (GCTs), we analyzed 40 primary and 3 metastatic testicular GCTs with regard to specific chromosomal losses and their parental origin. A high incidence of loss of heterozygosity (LOH) was demonstrated on chromosomes 1p, 3p, 11p, and 17p: 9/19 (47%), 18/39 (46%), 13/40 (33%) and 20/36 (56%), respectively. However, there was no correlation between the frequency of LOH on any chromosome and clinicopathological features. Regarding the parental origin of the lost allele at these chromosomes, preferential loss was not demonstrated in this study. To clarify the imprinting status in GCTs, we analyzed the allele-specific expression of the H19 gene, which is paternally imprinted on chromosome 11p. All of 11 tumors without LOH at this locus showed biallelic expression of H19. Based on previous work demonstrating the biallelic expression of H19 in primordial germ cells and spermatogonia in the mouse germ line, these results suggest that the biallelic expression of H19 in testicular GCTs reflects the characteristics of the original germ cells in which the imprinting marking has been erased and not established, rather than loss of imprinting during tumorigenesis. It is also possible that a failure to re-establish the imprinting might be an initial event which leads to testicular GCTs.

Alleles↗
PubMed2006

Expression profile of LIT1/KCNQ1OT1 and epigenetic status at the KvDMR1 in colorectal cancers.

The human chromosome region 11p15.5 contains a number of maternally and paternally imprinted genes, and the LIT1/KCNQ1OT1 locus acts as an imprinting center in the proximal domain of 11p15.5. Loss of imprinting (LOI) of LIT1 and its correlation with methylation status at a differentially methylated region, the KvDMR1, were investigated in 69 colorectal cancer tissue specimens. LIT1 expression profiles were also examined by RNA-fluorescence in situ hybridization in 13 colorectal cancer cell lines. In 69 colorectal cancer tissue specimens, LOI of LIT1 was observed in nine of the 17 (53%) informative cases. Moreover, LOI of LIT1 was only observed in tumor samples. In the cell lines, methylation status at the KvDMR1 correlated well with LIT1 expression profiles. Loss of expression of LIT1 also correlated with enrichment of H3 lysine 9 (H3-K9) dimethylation and reduction of H3 lysine 4 (H3-K4) dimethylation. Thus, LIT1 expression appears to be controlled by epigenetic modifications at the KvDMR1, although CDKN1C expression, which is considered to be controlled by LIT1, was not associated with epigenetic status at the KvDMR1 in some colorectal cancer cell lines. Therefore, these findings suggest that LOI of LIT1 via epigenetic disruption plays an important role in colorectal carcinogenesis, but it is not necessarily associated with CDKN1C expression.

Chromatin Immunoprecipitation↗
PubMed2005

CsrA and three redundant small RNAs regulate quorum sensing in Vibrio cholerae.

Bacteria communicate using a process called quorum sensing which involves production, secretion and detection of signalling molecules called autoinducers. Quorum sensing allows populations of bacteria to simultaneously regulate gene expression in response to changes in cell density. The human pathogen, Vibrio cholerae, uses a quorum-sensing circuit composed of parallel systems that transduce information through four redundant regulatory small RNAs (sRNAs) called quorum regulatory RNAs (Qrr) to control the expression of numerous genes, most notably those required for virulence. We show that the VarS/VarA two-component sensory system comprises an additional regulatory input controlling quorum-sensing-dependent gene expression in V. cholerae. VarS/VarA controls transcription of three previously unidentified small regulatory RNAs (sRNAs) that are similar to the sRNAs CsrB and CsrC of Escherichia coli. The three V. cholerae sRNAs, which we name CsrB, CsrC and CsrD, act redundantly to control the activity of the global regulatory protein, CsrA. The VarS/VarA-CsrA/BCD system converges with the V. cholerae quorum-sensing systems to regulate the expression of the Qrr sRNAs, and thus, the entire quorum-sensing regulon.

Adaptation, Physiological↗
PubMed2005

De-differentiation-derived mesenchymal stem cells demonstrate selective repression in H19 bioregulatory RNA gene expression.

Cellular de-differentiation can induce anticancer activity that makes cells resistant to carcinogenesis, but the molecular mechanism of this phenomenon has not been defined. To determine whether stable molecular changes develop in association with the process of de-differentiation, DNA microarray analyses were performed. These analyses compared control undifferentiated cells with three carcinogenesis-resistant clones of de-differentiated cells that were derived from mature adipocytes. The results of analysis of 6,000 genes and 6,000 ESTs establish that relative to control cells, all three de-differentiation-derived cell clones demonstrate that only one gene shows a consistent difference in expression. The expression of the H19 bioregulatory RNA is repressed an average of >fourfold in all de-differentiated cell clones. Real-time PCR analyses confirm these findings. This suggests that decreased H19 expression may account, at least in part, for the anticancer activity observed in de-differentiated cell clones.

Animals↗
PubMedDate not supplied

Klinefelter's syndrome: new and rapid diagnosis by PCR analysis of XIST gene expression.

Diagnosis of Klinefelter's syndrome relies on raised gonadotropin levels in serum, azoospermia, determination of sex chromatin in oral swabs and finally chromosome analysis in leukocyte cell culture. By this method the numerical chromosome aberration with a 47, XXY karyotype can be detected. However, diagnosis can be accelerated by demonstration of RNA expression of an X-linked gene, which serves as a marker for inactivation of the second and any further extra X chromosome in the cell. This so-called X-inactive-specific transcript (XIST) is transcribed exclusively from the inactive X chromosome. RNA was isolated both from Ficoll-prepared peripheral blood leukocytes and from total EDTA blood of Klinefelter patients and control persons. RNA was reverse transcribed and finally detected by the polymerase chain reaction (PCR) with XIST-specific sequences. The pyruvate dehydrogenase gene was used as a control gene for successful RNA preparation and reverse transcription. XIST transcripts could be detected in all blood samples from Klinefelter patients (n = 15, karyotype 47, XXY) and female persons (n = 3). Fertile men (n = 5) were negative for this transcript in peripheral blood. Thus, diagnosis of Klinefelter's syndrome can be accelerated without loss of sensitivity and specificity by detection of XIST expression in peripheral blood leukocytes.

Adult↗
PubMed2006

Refined association mapping for a quantitative trait: weight in the H19-IGF2-INS-TH region.

Previous analyses have provided evidence for one or more loci affecting body weight in the H19-IGF2-INS-TH region on chromosome 11p15. To identify the location of a possible causal locus or loci we applied association analysis by composite likelihood to a large cohort under the Malecot model for body weight. A random sample of 2731 men in the UK were typed for eleven single nucleotide polymorphisms (SNPs) in IGF2, two SNPs in H19, one SNP in INS and one microsatellite marker in the TH genes. Using F tests appropriate to small marker sets, the superiority of regression over correlation was confirmed. All the evidence for association came from IGF2, with P= 0.007 for height-adjusted weight and P= 0.019 for weight additionally adjusted for smoking and alcohol drinking. Although the estimated point location for the suspected causal variant was close to IGF2 ApaI, the 95% confidence and support intervals covered most of IGF2 but none of the other loci. Identification of the causal SNP or SNPs within IGF2 will require typing of more variants in this region.

Body Mass Index↗
PubMed1997

Duplication and polymorphism in the MHC: Alu generated diversity and polymorphism within the PERB11 gene family.

The PERB11 gene family has at least five members within the telomeric region of the MHC. The PERB11.1 and PERB11.2 genes are approximately 40 kb and 160 kb centromeric of HLA-B, respectively. Using continuous genomic sequence encompassing PERB11.1 and PERB11.2, we have found a large (approximately 25 kb) segmental duplication extending beyond the genes themselves and other potential coding sequences. The major difference between the segments are large indels which are predominantly Alu sequences. The Alu sequences within the duplicated segments have created diversity via the internal and 3' poly A-rich region. A sequence comparison of an Alu sequence between two different human ancestral haplotypes shows a high level of polymorphism, particularly in the poly A-rich regions. This study characterises the Alu sequences within the peri-PERB11.1 and peri-PERB11.2 duplicated segments in relation to diversity and polymorphism and as evolutionary markers.

Base Sequence↗
PubMed2003

Role of histone H3 lysine 27 methylation in X inactivation.

The Polycomb group (PcG) protein Eed is implicated in regulation of imprinted X-chromosome inactivation in extraembryonic cells but not of random X inactivation in embryonic cells. The Drosophila homolog of the Eed-Ezh2 PcG protein complex achieves gene silencing through methylation of histone H3 on lysine 27 (H3-K27), which suggests a role for H3-K27 methylation in imprinted X inactivation. Here we demonstrate that transient recruitment of the Eed-Ezh2 complex to the inactive X chromosome (Xi) occurs during initiation of X inactivation in both extraembryonic and embryonic cells and is accompanied by H3-K27 methylation. Recruitment of the complex and methylation on the Xi depend on Xist RNA but are independent of its silencing function. Together, our results suggest a role for Eed-Ezh2-mediated H3-K27 methylation during initiation of both imprinted and random X inactivation and demonstrate that H3-K27 methylation is not sufficient for silencing of the Xi.

Animals↗
PubMed2004

Transgenic RNAi reveals essential function for CTCF in H19 gene imprinting.

The imprinted regulation of H19 and Insulin-like growth factor 2 expression involves binding of the vertebrate insulator protein, CCCTC binding factor (CTCF), to the maternally hypomethylated differentially methylated domain (DMD). How this hypomethylated state is maintained during oogenesis and the role of CTCF, if any, in this process are not understood. With the use of a transgenic RNA interference (RNAi)-based approach to generate oocytes with reduced amounts of CTCF protein, we found increased methylation of the H19 DMD and decreased developmental competence of CTCF-deficient oocytes. Our results suggest that CTCF protects the H19 DMD from de novo methylation during oocyte growth and is required for normal preimplantation development.

Actins↗
PubMed2004

Reactivation of the paternal X chromosome in early mouse embryos.

It is generally accepted that paternally imprinted X inactivation occurs exclusively in extraembryonic lineages of mouse embryos, whereas cells of the embryo proper, derived from the inner cell mass (ICM), undergo only random X inactivation. Here we show that imprinted X inactivation, in fact, occurs in all cells of early embryos and that the paternal X is then selectively reactivated in cells allocated to the ICM. This contrasts with more differentiated cell types where X inactivation is highly stable and generally irreversible. Our observations illustrate that an important component of genome plasticity in early development is the capacity to reverse heritable gene silencing decisions.

Acetylation↗
PubMed2003

Epigenetic dynamics of imprinted X inactivation during early mouse development.

The initiation of X-chromosome inactivation is thought to be tightly correlated with early differentiation events during mouse development. Here, we show that although initially active, the paternal X chromosome undergoes imprinted inactivation from the cleavage stages, well before cellular differentiation. A reversal of the inactive state, with a loss of epigenetic marks such as histone modifications and polycomb proteins, subsequently occurs in cells of the inner cell mass (ICM), which give rise to the embryo-proper in which random X inactivation is known to occur. This reveals the remarkable plasticity of the X-inactivation process during preimplantation development and underlines the importance of the ICM in global reprogramming of epigenetic marks in the early embryo.

Acetylation↗
PubMed2005

Loss of imprinting of Igf2 alters intestinal maturation and tumorigenesis in mice.

Loss of imprinting (LOI) of the insulin-like growth factor II gene (IGF2) is an epigenetic alteration that results in a modest increase in IGF2 expression, and it is present in the normal colonic mucosa of about 30% of patients with colorectal cancer. To investigate its role in intestinal tumorigenesis, we created a mouse model of Igf2 LOI by crossing female H19+/- mice with male Apc+/Min mice. Mice with LOI developed twice as many intestinal tumors as did control littermates. Notably, these mice also showed a shift toward a less differentiated normal intestinal epithelium, reflected by an increase in crypt length and increased staining with progenitor cell markers. A similar shift in differentiation was seen in the normal colonic mucosa of humans with LOI. Thus, altered maturation of nonneoplastic tissue may be one mechanism by which epigenetic changes affect cancer risk.

Adenoma↗
PubMed2006

Transient homologous chromosome pairing marks the onset of X inactivation.

Mammalian X inactivation turns off one female X chromosome to enact dosage compensation between XX and XY individuals. X inactivation is known to be regulated in cis by Xite, Tsix, and Xist, but in principle the two Xs must also be regulated in trans to ensure mutually exclusive silencing. Here, we demonstrate that interchromosomal pairing mediates this communication. Pairing occurs transiently at the onset of X inactivation and is specific to the X-inactivation center. Deleting Xite and Tsix perturbs pairing and counting/choice, whereas their autosomal insertion induces de novo X-autosome pairing. Ectopic X-autosome interactions inhibit endogenous X-X pairing and block the initiation of X-chromosome inactivation. Thus, Tsix and Xite function both in cis and in trans. We propose that Tsix and Xite regulate counting and mutually exclusive choice through X-X pairing.

Animals↗
PubMed2006

CTCF mediates interchromosomal colocalization between Igf2/H19 and Wsb1/Nf1.

Gene transcription may be regulated by remote enhancer or insulator regions through chromosome looping. Using a modification of chromosome conformation capture (3C) and fluorescence in situ hybridization, we found that one allele of the insulin-like growth factor 2 (Igf2)/H19 imprinting control region (ICR) on chromosome 7 colocalized with one allele of Wsb1/Nf1 on chromosome 11. Omission of CCCTC-binding factor (CTCF) or deletion of the maternal ICR abrogated this association and altered Wsb1/Nf1 gene expression. These findings demonstrate that CTCF mediates an interchromosomal association, perhaps by directing distant DNA segments to a common transcription factory, and the data provide a model for long-range allele-specific associations between gene regions on different chromosomes that suggest a framework for DNA recombination and RNA trans-splicing.

Alleles↗