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PubMed1998

Severe phenotype resulting from an active ring X chromosome in a female with a complex karyotype: characterisation and replication study.

We report on the characterisation of a complex chromosome rearrangement, 46,X,del(Xq)/47,X,del(Xq),+r(X), in a female newborn with multiple malformations. Cytogenetic and molecular methods showed that the del(Xq) contains the XIST locus and is non-randomly inactivated in all metaphases. The tiny r(X) chromosome gave a positive FISH signal with UBE1, ZXDA, and MSN cosmid probes, but not with a XIST cosmid probe. Moreover, it has an active status, as shown by a very short (three hour) terminal BrdU pulse followed by fluorescent anti-BrdU antibody staining. The normal X is of paternal origin and both rearranged chromosomes originate from the same maternal chromosome. We suggest that both abnormal chromosomes result from the three point breakage of a maternal isodicentric idic(X)(q21.1). Finally, the phenotype of our patient is compared to other published cases and, despite the absence of any 45,X clone, it appears very similar to those with a 45,X/46,X,r(X) karyotype where the tiny r(X) is active.

Abnormalities, Multiple↗
PubMed2003

Silencing of CDKN1C (p57KIP2) is associated with hypomethylation at KvDMR1 in Beckwith-Wiedemann syndrome.

CONTEXT: Beckwith-Wiedemann syndrome (BWS) arises by several genetic and epigenetic mechanisms affecting the balance of imprinted gene expression in chromosome 11p15.5. The most frequent alteration associated with BWS is the absence of methylation at the maternal allele of KvDMR1, an intronic CpG island within the KCNQ1 gene. Targeted deletion of KvDMR1 suggests that this locus is an imprinting control region (ICR) that regulates multiple genes in 11p15.5. Cell culture based enhancer blocking assays indicate that KvDMR1 may function as a methylation modulated chromatin insulator and/or silencer. OBJECTIVE: To determine the potential consequence of loss of methylation (LOM) at KvDMR1 in the development of BWS. METHODS: The steady state levels of CDKN1C gene expression in fibroblast cells from normal individuals, and from persons with BWS who have LOM at KvDMR1, was determined by both real time quantitative polymerase chain reaction (qPCR) and ribonuclease protection assay (RPA). Methylation of the CDKN1C promoter region was assessed by Southern hybridisation using a methylation sensitive restriction endonuclease. RESULTS: Both qPCR and RPA clearly demonstrated a marked decrease (86-93%) in the expression level of the CDKN1C gene in cells derived from patients with BWS, who had LOM at KvDMR1. Southern analysis indicated that downregulation of CDKN1C in these patients was not associated with hypermethylation at the presumptive CDKN1C promoter. CONCLUSIONS: An epimutation at KvDMR1, the absence of maternal methylation, causes the aberrant silencing of CDKN1C, some 180 kb away on the maternal chromosome. Similar to mutations at this locus, this silencing may give rise to BWS.

Beckwith-Wiedemann Syndrome↗
PubMed2004

Spinocerebellar ataxia type 8 in Scotland: genetic and clinical features in seven unrelated cases and a review of published reports.

OBJECTIVES: To establish whether the DNA expansion linked to spinocerebellar ataxia type 8 (SCA 8) is associated with ataxia in Scotland; to clarify the range of associated clinical phenotypes; and to compare the findings with previous reports. METHODS: DNA was screened from 1190 anonymised controls, 137 subjects who had tested negative for Huntington's disease, 176 with schizophrenia, and 173 with undiagnosed ataxia. Five unrelated ataxic patients with the SCA 8 expansion and a sixth identified subsequently had clinical and psychometric assessment; the clinical features were available in a seventh. A systematic search for other reports of SCA 8 was undertaken. RESULTS: Over 98% of SCA 8 CTA/CTG repeat lengths fell between 14 and 40. Repeat lengths over 91 were observed in three healthy controls (0.12%), two patients with suspected Huntington's disease (0.73%), and six ataxic subjects (1.74%; p<0.0005 v healthy controls). Repeat lengths over 100 occurred in five ataxic subjects but in only one control. All seven symptomatic subjects with the SCA 8 expansion had a cerebellar syndrome; four had upper motor neurone signs; and 5/6 assessed had cognitive complaints. There was personality change in two and mood disturbance in three. In published reports, SCA 8 repeat lengths over 91 occurred in approximately 0.5% of the healthy population but were over-represented among ataxic patients (3.4%; p<0.0001). The predominant clinical phenotype was cerebellar, with pyramidal signs in 50%, and neuropsychiatric features in some cases. CONCLUSIONS: SCA 8 expansion is a risk factor for a cerebellar syndrome, often associated with upper motor neurone and neuropsychiatric features. The expansion occurs unexpectedly often in the general population.

Adolescent↗
PubMed1997

The product of the imprinted H19 gene is an oncofetal RNA.

AIMS/BACKGROUND: The H19 gene is an imprinted, maternally expressed gene in humans. It is tightly linked and coregulated with the imprinted, paternally expressed gene of insulin-like growth factor 2. The H19 gene product is not translated into protein and functions as an RNA molecule. Although its role has been investigated for more than a decade, its biological function is still not understood fully. H19 is abundantly expressed in many tissues from early stages of embryogenesis through fetal life, and is down regulated postnatally. It is also expressed in certain childhood and adult tumours. This study was designed to screen the expression of H19 in human cancer and its relation to the expression of H19 in the fetus. METHODS: Using in situ hybridisation with a [35S] labelled probe, H19 mRNA was detected in paraffin wax sections of fetal tissues from the first and second trimesters of pregnancy and of a large array of human adult and childhood tumours arising from these tissues. RESULTS: The H19 gene is expressed in tumours arising from tissues which express this gene in fetal life. Its expression in the fetus and in cancer is closely linked with tissue differentiation. CONCLUSIONS: Based on these and previous data, H19 is neither a tumour suppressor gene nor an oncogene. Its product is an oncofetal RNA. The potential use of this RNA as a tumour marker should be evaluated.

Biomarkers, Tumor↗
PubMed2000

The imprinted H19 gene is a marker of early recurrence in human bladder carcinoma.

AIMS: To investigate the expression of the imprinted oncofetal H19 gene in human bladder carcinoma and to examine the possibility of using it as a tumour marker, similar to other oncofetal gene products. METHODS: In situ hybridisation for H19 RNA was performed on 61 first biopsies of bladder carcinoma from Hadassah Medical Centre in Jerusalem. The intensity of the reaction and the number of tumour cells expressing H19 in each biopsy were evaluated in 56 patients, excluding biopsies with carcinoma in situ. The medical files were searched for demographic data and disease free survival. RESULTS: More than 5% of cells expressed H19 in 47 of the 56 (84%) biopsies. There was a decrease in the number of cells expressing H19 with increasing tumour grade (loss of differentiation) (p = 0.03). Disease free survival from the first biopsy to first recurrence was significantly shorter in patients with tumours having a larger fraction of H19 expressing cells, controlling for tumour grade. This was also supported by the selective analysis of tumour recurrence in patients with grade I tumours. CONCLUSIONS: It might be possible to use H19 as a prognostic tumour marker for the early recurrence of bladder cancer. In addition, for the gene therapy of bladder carcinoma that is based on the transcriptional regulatory sequences of H19, the expression of H19 in an individual biopsy could be considered a predictive tumour marker for selecting those patients who would benefit from this form of treatment.

Aged↗
PubMed2001

Imprinting and deviation from Mendelian transmission ratios.

Deviations from a Mendelian 1:1 transmission ratio have been observed in human and mouse chromosomes. With few exceptions, the underlying mechanism of the transmission-ratio distortion remains obscure. We tested a hypothesis that grandparental-origin dependent transmission-ratio distortion is related to imprinting and possibly results from the loss of embryos which carry imprinted genes with imprinting marks that have been incorrectly reset. We analyzed transmission of alleles in four regions of the human genome that carry imprinted genes presumably critical for normal embryonic growth and development: 11p15.5 (H19, IGF2, HASH2, etc.), 11p13 (WT1), 7p11-12 (GRB10), and 6q25-q27 (IGF2R), among the offspring of 31 three-generation Centre d'Etude de polymorphism Humain (CEPH) families. Deviations from expected 1:1 ratios were found in the maternal chromosomes for regions 11p15.5, 11p13, and 6q25-27 and in the paternal chromosomes for regions 11p15 and 7p11-p12. The likelihood of the results was assessed empirically to be statistically significant (p = 0.0008), suggesting that the transmission ratios in the imprinted regions significantly deviated from 1:1. We did not find deviations from a 1:1 transmission ratio in imprinted regions that are not crucial for embryo viability (13q14 and 15q11-q13). The analysis of a larger set of 51 families for the 11p15.5 region suggests that there is heterogeneity among the families with regard to the transmission of 11p15.5 alleles. The results of this study are consistent with the hypothesis that grandparental-origin dependent transmission-ratio distortion is related to imprinting and embryo loss.

Alleles↗
PubMed2002

Xist RNA and the mechanism of X chromosome inactivation.

Dosage compensation in mammals is achieved by the transcriptional inactivation of one X chromosome in female cells. From the time X chromosome inactivation was initially described, it was clear that several mechanisms must be precisely integrated to achieve correct regulation of this complex process. X-inactivation appears to be triggered upon differentiation, suggesting its regulation by developmental cues. Whereas any number of X chromosomes greater than one is silenced, only one X chromosome remains active. Silencing on the inactive X chromosome coincides with the acquisition of a multitude of chromatin modifications, resulting in the formation of extraordinarily stable facultative heterochromatin that is faithfully propagated through subsequent cell divisions. The integration of all these processes requires a region of the X chromosome known as the X-inactivation center, which contains the Xist gene and its cis-regulatory elements. Xist encodes an RNA molecule that plays critical roles in the choice of which X chromosome remains active, and in the initial spread and establishment of silencing on the inactive X chromosome. We are now on the threshold of discovering the factors that regulate and interact with Xist to control X-inactivation, and closer to an understanding of the molecular mechanisms that underlie this complex process.

Animals↗
PubMed2005

Loss of the inactive X chromosome and replication of the active X in BRCA1-defective and wild-type breast cancer cells.

In females, X chromosome inactivation (XCI) begins with the expression of the XIST gene from the X chromosome destined to be inactivated (Xi) and the coating of XIST RNA in cis. It has recently been reported that this process is supported by the product of the BRCA1 tumor suppressor gene and that BRCA1-/- cancers show Xi chromatin structure defects, thus suggesting a role of XCI perturbation in BRCA1-mediated tumorigenesis. Using a combined genetic and epigenetic approach, we verified the occurrence of XCI in BRCA1-/- and BRCA1wt breast cancer cell lines. It was ascertained that the Xi was lost in all cancer cell lines, irrespective of the BRCA1 status and that more than one active X (Xa) was present. In addition, no epigenetic silencing of genes normally subjected to XCI was observed. We also evaluated XIST expression and found that XIST may be occasionally transcribed also from Xa. Moreover, in one of the BRCA1wt cell line the restoring of XIST expression using a histone deacetylase inhibitor, did not lead to XCI. To verify these findings in primary tumors, chromosome X behavior was investigated in a few BRCA1-associated and BRCA1-not associated primary noncultured breast carcinomas and the results mirrored those obtained in cancer cell lines. Our findings indicate that the lack of XCI may be a frequent phenomenon in breast tumorigenesis, which occurs independently of BRCA1 status and XIST expression and is due to the loss of Xi and replication of Xa and not to the reactivation of the native Xi.

Breast Neoplasms↗
PubMed2006

DNA methylation changes after 5-aza-2'-deoxycytidine therapy in patients with leukemia.

5-Aza-2'-deoxycytidine (decitabine) is postulated to have clinical activity in myeloid leukemias via its ability to inhibit DNA methylation. To study this, we examined DNA methylation in patients with leukemia treated with decitabine. Five days after the treatment, total genomic 5-methylcytosine/cytosine decreased on average by 14% (from 4.3% to 3.7%), whereas methylation of repetitive DNA elements showed a mean decrease of 9% and 16% for Alu and long interspersed nucleotide elements, respectively. Methylation decreased linearly with increasing doses between 5 and 20 mg/m(2)/d (r = 0.88; P = 0.05) but showed a plateau above that. Hypomethylation correlated with response in patients with acute myelogenous leukemia treated with low doses (5-20 mg/m(2)/d), but patients with chronic myelogenous leukemia treated with high doses (100-180 mg/m(2)/d) showed no such correlation. Aberrant methylation of p15 (>10%) was found in 27% of patients, and 80% of these showed a decrease by at least one third, but this did not correlate with response. The imprinted gene H19 showed little change in methylation after decitabine. In conclusion, we show dose-dependent hypomethylation after decitabine at low doses. Increasing the dose, which has been shown previously to result in a reduced response rate, was not accompanied by further hypomethylation.

Adult↗
PubMed2005

Genomic profiling maps loss of heterozygosity and defines the timing and stage dependence of epigenetic and genetic events in Wilms' tumors.

To understand genetic and epigenetic pathways in Wilms' tumors, we carried out a genome scan for loss of heterozygosity (LOH) using Affymetrix 10K single nucleotide polymorphism (SNP) chips and supplemented the data with karyotype information. To score loss of imprinting (LOI) of the IGF2 gene, we assessed DNA methylation of the H19 5' differentially methylated region (DMR). Few chromosomal regions other than band 11p13 (WT1) were lost in Wilms' tumors from Denys-Drash and Wilms' tumor-aniridia syndromes, whereas sporadic Wilms' tumors showed LOH of several regions, most frequently 11p15 but also 1p, 4q, 7p, 11q, 14q, 16q, and 17p. LOI was common in the sporadic Wilms' tumors but absent in the syndromic cases. The SNP chips identified novel centers of LOH in the sporadic tumors, including a 2.4-Mb minimal region on chromosome 4q24-q25. Losses of chromosomes 1p, 14q, 16q, and 17p were more common in tumors presenting at an advanced stage; 11p15 LOH was seen at all stages, whereas LOI was associated with early-stage presentation. Wilms' tumors with LOI often completely lacked LOH in the genome-wide analysis, and in some tumors with concomitant 16q LOH and LOI, the loss of chromosome 16q was mosaic, whereas the H19 DMR methylation was complete. These findings confirm molecular differences between sporadic and syndromic Wilms' tumors, define regions of recurrent LOH, and indicate that gain of methylation at the H19 DMR is an early event in Wilms' tumorigenesis that is independent of chromosomal losses. The data further suggest a biological difference between sporadic Wilms' tumors with and without LOI.

Blotting, Northern↗
PubMed2006

Frequent IGF2/H19 domain epigenetic alterations and elevated IGF2 expression in epithelial ovarian cancer.

Overexpression of the imprinted insulin-like growth factor-II (IGF2) is a prominent characteristic of gynecologic malignancies. The purpose of this study was to determine whether IGF2 loss of imprinting (LOI), aberrant H19 expression, and/or epigenetic deregulation of the IGF2/H19 imprinted domain contributes to elevated IGF2 expression in serous epithelial ovarian tumors. IGF2 LOI was observed in 5 of 23 informative serous epithelial ovarian cancers, but this did not correlate with elevated expression of IGF2 H19 RNA expression levels were also found not to correlate with IGF2 transcript levels. However, we identified positive correlations between elevated IGF2 expression and hypermethylation of CCCTC transcription factor binding sites 1 and 6 at the H19 proximal imprint center (P = 0.05 and 0.02, respectively). Hypermethylation of CCCTC transcription factor sites 1 and 6 was observed more frequently in cancer DNA compared with lymphocyte DNA obtained from women without malignancy (P < 0.0001 for both sites 1 and 6). Ovarian cancers were also more likely to exhibit maternal allele-specific hypomethylation upstream of the imprinted IGF2 promoters when compared with normal lymphocyte DNA (P = 0.004). This is the same region shown previously to be hypomethylated in colon cancers with IGF2 LOI, but this was not associated with LOI in ovarian cancers. Elevated IGF2 expression is a frequent event in serous ovarian cancer and this occurs in the absence of IGF2 LOI. These data indicate that the epigenetic changes observed in these cancers at the imprint center may contribute to IGF2 overexpression in a novel mechanistic manner.

Alleles↗
PubMed2006

Down syndrome candidate region 1 isoform 1 mediates angiogenesis through the calcineurin-NFAT pathway.

Down syndrome candidate region 1 (DSCR1) is one of more than 50 genes located in a region of chromosome 21 that has been implicated in Down syndrome. DSCR1 can be expressed as four isoforms, one of which, isoform 4 (DSCR1-4), has recently been found to be strongly induced by vascular endothelial growth factor A (VEGF-A(165)) and to provide a negative feedback loop that inhibits VEGF-A(165)-induced endothelial cell proliferation in vitro and angiogenesis in vivo. We report here that another DSCR1 isoform, DSCR1-1L, is also up-regulated by VEGF-A(165) in cultured endothelial cells and is strongly expressed in several types of pathologic angiogenesis in vivo. In contrast to DSCR1-4, the overexpression of DSCR1-1L induced the proliferation and activation of the transcription factor NFAT in cultured endothelial cells and promoted angiogenesis in Matrigel assays in vivo, even in the absence of VEGF-A. Similarly, small interfering RNAs specific for DSCR1-1L and DSCR1-4 had opposing inhibitory and stimulatory effects, respectively, on these same functions. DSCR1-4 is thought to inhibit angiogenesis by inactivating calcineurin, thereby preventing activation and nuclear translocation of NFAT, a key transcription factor. In contrast, DSCR1-1L, regulated by a different promoter than DSCR1-4, activates NFAT and its proangiogenic activity is inhibited by cyclosporin, an inhibitor of calcineurin. In sum, DSCR1-1L, unlike DSCR1-4, potently activates angiogenesis and could be an attractive target for antiangiogenesis therapy.

Active Transport, Cell Nucleus↗
PubMedDate not supplied

Genomic imprinting of IGF-II and H19 in adult human pancreatic tissues.

BACKGROUND/AIM: Genomic imprinting is a chromosomal modification causing differential expression of maternal and paternal alleles. Loss of imprinting (LOI) of IGF-II and H19 has been suggested to be an early oncogenic event in cancerogenesis. Aim of the present study was to describe the status of IGF-II and H19 imprinting in adult human pancreatic tissues. METHODS: Allele-specific gene expression was studied using RNA and DNA from human pancreatic cancer, chronic pancreatitis, and normal pancreas tissues heterozygous for ApaI (IGF-II) or RsaI (H19) restriction fragment length polymorphism. Reverse-transcriptase polymerase chain reaction products were digested with either ApaI or RsaI and analyzed on agarose gels to study the status of allelic expression. The expression level of H19 and IGF-II was studied on Northern blots or by polymerase chain reaction. RESULTS: H19 was imprinted in normal pancreas and in chronic pancreatitis. H19 LOI was observed in 1 of 4 informative cancer tissues and was not associated with increased H19 transcript levels. Biallelic expression of IGF-II was found in 6 of 10 informative cancer tissues and in 6 of 9 informative normal tissues. In chronic pancreatitis, the IGF-II gene was imprinted in all informative samples. IGF-II mRNA was not overexpressed in the tissues showing LOI. CONCLUSION: Low frequencies of H19 LOI and the lack of correlation between biallelic expression and overexpression observed for both H19 and IGF-II suggest that LOI of H19 and IGF-II is not a relevant oncogenic factor during human exocrine pancreatic cancerogenesis.

Adenocarcinoma↗
PubMed1998

X-chromosome inactivation: a repeat hypothesis.

Recent work has shown that X-chromosome inactivation is brought about by Xist mRNA, which coats the inactive X-chromosome. This paper presents a hypothesis on the function of this RNA. It is suggested that interspersed repetitive elements of the LINE type, in which the X-chromosome is particularly rich, act as booster elements to promote the spread of Xist mRNA. Contact with this RNA causes the LINE elements to be sensed as repeated elements by the cell's system for repeat-induced gene silencing. This leads to the silencing of these elements and the intervening unique sequences by their conversion to heterochromatin.

Animals↗
PubMed1998

Position effect of translocations involving the inactive X chromosome: physical linkage to XIC/XIST does not lead to long-range de novo inactivation in human differentiated cells.

Given the reported long-range cis-inactivating effect of the XIST gene in early embryonic development and the lack of requirement of X-chromosome-specific elements for propagating the inactive state, there exists the possibility of cis inactivation of autosomal material after de novo translocation to an inactive X chromosome (Xi) in differentiated cells. We have analyzed de novo radiation-induced translocations between the Xi and autosomes to study the maintenance and spreading of X-chromosome inactivation (X inactivation) in relation to the position of the X-inactivation center (XIC)/XIST in differentiated cells. Autosome/Xi translocations were detected by fluorescence in situ hybridization (FISH). The activation status of the chromosomes involved in the translocation was determined by simultaneous immunocytogenetic studies using antibodies against either BrdU incorporated at late S phase or acetylated histone H4. The position of XIC/XIST in the reciprocal products of the translocation was determined by XIST-specific FISH and computer enhancement. In other experiments, the Xq13 region carrying XIC/XIST was localized by computer enhancement of the DAPI banding pattern. Our study in differentiated cells provides a visual demonstration that physical separation from XIC/XIST does not result in reactivation of inactive X-chromosome material and that X inactivation is not spread to the translocated autosomes irrespective of the position of XIC/XIST. This observation suggests that physical linkage to XIC/XIST does not lead to de novo inactivation of autosomal material.

Cell Differentiation↗
PubMed2000

Histone macroH2A1.2 is concentrated in the XY compartment of mammalian male meiotic nuclei.

We show here that histone macroH2A1.2 concentrates at the transcriptionally silent XY body, normally being formed during male meiosis in the mouse. A similar accumulation has earlier been observed on the inactive X chromosomes of somatic adult female mammalian cells by Costanzi and Pehrson (1998). This correspondence in the nature of heterochromatinization of the X chromosomes in males and females adds another property of X chromosome inactivation that is shared by males and females at different phases of their life cycle.

Animals↗