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PubMed2000

Imprinting of insulin-like growth factor 2 is modulated during hematopoiesis.

The transcription of insulin-like growth factor 2 (IGF-2) is affected by genomic imprinting, a multistep process through which the parental origin of a gene influences its transcription. The maternal copy of IGF-2 is silenced in most human tissues, but in the choroid plexus and the adult liver both alleles of IGF-2 are expressed. This study shows that though in peripheral blood mononuclear cells IGF-2 shows paternal allele-specific expression, in total bone marrow both alleles are transcribed. This modulation of imprinting is not attributable to use of the P1 promoter, because transcription from the P3 promoter occurred from both alleles. These results suggest that transcriptional recognition of the IGF-2 imprint can be modulated during hematopoiesis and may facilitate the development of in vitro model systems to study the transcriptional recognition of a genomic imprint.

Adolescent↗
PubMed2000

Altered expression of estrogen receptor coregulators during human breast tumorigenesis.

The hypothesis that altered expression of specific coactivators/repressors of the estrogen receptor occurs during human breast tumorigenesis in vivo is examined in this study. Using in situ hybridization and reverse transcription-PCR assays, the expression of two coactivators (SRA and AIB1) and one repressor (REA) of the estrogen receptor was compared between matched breast tumors and adjacent normal human breast tissue. The levels of SRA and AIB1 mRNA were increased in tumors compared with normal tissues (n = 19; Wilcoxon matched pairs test; P < 0.01). In contrast, the expression of REA mRNA was not different between tumors and normal tissues (n = 19; Wilcoxon; P = 0.110). The ratios of AIB1:REA and SRA:REA were higher (Wilcoxon; P < 0.05) in tumors compared with normal tissues. Furthermore, SRA:AIB1 was higher (Wilcoxon; P = 0.0058) in tumors compared with normal tissues. Although our study is small, these data are consistent with the above hypothesis and suggest that such alterations may have a role in the altered estrogen action occurring during breast tumorigenesis.

Breast↗
PubMed2000

Dynamic readjustment of parental methylation patterns of the 5'-flank of the mouse H19 gene during in vitro organogenesis.

Gametic marks are stably propagated in order to manifest parent of origin-specific expression patterns of imprinted genes in the developing conceptus. Although the character of the imprint has not yet been fully elucidated, there is compelling evidence that it involves a methylation mark. This is exemplified by a region upstream of the H19 gene, which is not only methylated in a parent of origin-specific manner, but also regulates the silencing of the maternal Igf2 and paternal H19 alleles, respectively. We show here that the parental-specific methylation patterns within the differentially methylated domain (DMD) are perturbed in the soma during in vitro organogenesis. Under these conditions, the paternal DMD allele becomes partially demethylated, whereas the maternal DMD allele gains methylation. Despite these effects, there were no changes in allelic Igf2 or H19 expression patterns in the embryo. Finally, we show that although TSA derepresses the paternal H19 allele in ectoplacental cone when in vitro developed, there is no discernible effect on the methylation status of the paternally inherited 5'-flank in comparison to control samples. Collectively, this data demonstrates that the parental mark is sensitive to a subset of environmental cues and that a certain degree of plasticity of the gametic mark is tolerated without affecting the manifestation of the imprinted state.

Alleles↗
PubMed2000

[A familial case of spinocerebellar ataxia type 8 (SCA 8)--its clinical findings and an issue about the genetic basis].

We report a 28-year-old woman with spinocerebellar ataxia type 8 (SCA 8). This patient began to exhibit dysarthria at the age of 19. At the age of 25, she fell and hit her head while drunk and then a neurosurgeon found that her cerebellum was atrophic on cranial CT and MRI. Neurological examination on admission to our hospital revealed ataxic speech, limb ataxia and mild hyperreflexia without Babinski's sign. Cranial MRI showed only mild atrophy of the cerebellar hemispheres and vermis. Based on the results of genetic analysis, which showed expanded CTG repeats[(CTA) 13 (CTG) 5 (CCG) 4 (CTG) 124] on the SCA 8 locus at 13q21, she was diagnosed as having SCA 8. As clinical signs of SCA 8, Koob et al. reported limb spasticity and diminished vibration perception including cerebellar ataxia. Furthermore, Hirose et al. and Satoh et al. reported cases showing involuntary movements such as myoclonus or chorea including cerebellar ataxia. Our case and Ikeda's cases presented a pure cerebellar phenotype. We think that SCA 8 exhibits clinical heterogeneity. On the other hand, Stevanin et al. and Worth et al. expressed doubt as to whether the SCA 8 locus at 13q21 is the gene actually responsible for autosomal dominant cerebellar ataxia (ADCA). We conclude that it is necessary to accumulate additional case reports, and to further investigate the relationship between the clinical findings and the results of genetic analysis in order to determine whether or not the SCA 8 locus at 13q21 is the genetic basis for ADCA.

Adult↗
PubMed2001

Loss of imprinting of insulin-like growth factor-II in Wilms' tumor commonly involves altered methylation but not mutations of CTCF or its binding site.

Loss of imprinting (LOI) is the most common molecular abnormality in Wilms' tumor (WT), other embryonal cancers, and most other tumor types. LOI in WT involves activation of the normally silent maternal allele of the insulin-like growth factor-II (IGF2) gene, silencing of the normally active maternal allele of the H19 gene, and aberrant methylation of a differentially methylated region (DMR) upstream of the maternal copy of H19. Recently, the transcription factor CTCF, which binds to the H19 DMR, has been implicated in the maintenance of H19 and IGF2 imprinting. Here, we show that mutations in the CTCF gene or in the H19 DMR do not occur at significant frequency in WT, nor is there transcriptional silencing of CTCF. We also confirm that methylation of the H19 DMR in WT with LOI includes the CTCF core consensus site. However, some WTs with normal imprinting of IGF2 also show aberrant methylation of CTCF binding sites, indicating that methylation of these sites is necessary but not sufficient for LOI in WT.

Alleles↗
PubMed2001

Characterization of the 13q14 tumor suppressor locus in CLL: identification of ALT1, an alternative splice variant of the LEU2 gene.

Chromosome 13q14 deletions constitute the most common genetic abnormality in chronic lymphocytic leukemia (CLL). To identify the putative tumor suppressor gene targeted by 13q14 genomic loss, we completely sequenced and characterized a segment of 790 kb at 13q14 spanning the minimal region of loss in CLL. Transcribed sequences in the region were identified through database homology searches and exon-prediction analysis. Two-hundred kb at the centromeric end of the sequence contain five CpG islands, three previously identified genes LEU5/RFP2, LEU2, and LEU1, seven of seven EST clusters composed of >10 ESTs, and a large number of predicted exons. Homology searches against the mouse EST database have allowed us to identify a highly conserved alternative first exon of the LEU2 gene, giving rise to a novel transcript, ALT1 (GenBank accession no. AF380424), which originates within a G+C region in the vicinity of the D13S272 marker. Two novel 3' exons of LEU2 were also identified and are present in both LEU2 and ALT1 transcripts. However, we have not identified any mutations in leukemia cases, or alterations in expression of mRNAs in the region, that might directly implicate these mRNAs in the pathology of CLL. The centromeric end of the sequence, where all reported genes are located, contains twice the expected amount of ALU repeats, whereas the telomeric end is LINE1 rich and contains four LINE1 elements longer than 4 kb, including two full-length LINE1 sequences. This feature of the sequence may favor the occurrence of chromosomal rearrangements and may confer instability to the region, resulting in deletions that may inactivate an as yet unidentified tumor suppressor.

Alternative Splicing↗
PubMedDate not supplied

[Type 8 spinocerebellar ataxia. A report of a family].

INTRODUCTION: Over the past decade, from the genetic point of view, several of the entities included in the group of hereditary ataxias have been identified. We report a Spanish family with type 8 spinocerebellar ataxia (SCA8), one of the most recent hereditary ataxias to be described from the clinical and genetic points of view. CLINICAL CASE: A 59 year old woman consulted us complaining of progressive dysarthria and unsteady gait. The only abnormal findings on neurological examination were those of cerebellar involvement. The patient s mother had a similar condition, characterized by difficulty in speaking which started when she was 62 years old and progressed to anarthria. Cranial magnetic resonance showed the presence of cerebellar atrophy with no signs of atrophy of the brainstem. On electromyographic studies there were no signs of neuropathy. Visual, auditory and sensory evoked potentials were normal. Genetic studies showed expansion of trinucleotide CTG (112 repetitions in the expanded allele and 28 repetitions in the normal allele) on the gene responsible for SCA8. CONCLUSION: SCA8 should be included in the differential diagnosis of progressive cerebellar syndromes, especially when changes in speech predominate with regard to other cerebellar signs.

Atrophy↗
PubMed2001

Multipoint imprinting analysis indicates a common precursor cell for gonadal and nongonadal pediatric germ cell tumors.

Pediatric germ cell tumors (GCTs) commonly arise at extragonadal sites. It has been proposed that nongonadal GCTs arise from ectopic primordial germ cells that have aberrantly migrated during embryogenesis. During a time between their migration and development to mature gametes, primordial germ cells are characterized by their lack of imprinting, which can be assessed by the evaluation of allelic gene expression and DNA methylation in differentially methylated control regions. To elucidate the cellular origin of nongonadal GCTs, we evaluated the imprinting status of 21 gonadal and 21 nongonadal pediatric GCTs. Allele-specific H19 and IGF-2 expression was assessed with reverse transcription-PCR followed by digestion at polymorphic restriction sites. DNA methylation was evaluated after bisulfite modification, PCR amplification, and restriction digestion at a consistently methylated CpG dinucleotide within the 5' flanking region of the SNRPN gene. These results were compared with genetic gains and losses determined by comparative genomic hybridization. Seven of 15 informative tumors showed biallelic H19 expression, and 8 of 17 informative tumors showed biallelic IGF-2 expression. The frequency of biallelic gene expression was comparable in gonadal and nongonadal GCTs. Sixteen of 19 gonadal GCTs and 17 of 21 nongonadal GCTs showed absence of methylation of SNRPN consistent with loss of imprinting. One testicular GCT and three nongonadal GCTs showed a somatic methylation pattern. Two ovarian teratomas and one mediastinal teratoma showed only methylated SNRPN, consistent with entry into meiosis. Twenty-one of 22 non-GCT control samples showed a somatic methylation pattern. Gonadal and nongonadal germ cell tumors are derived from primordial germ cells that have consistently lost the imprinting of SNRPN and partly lost imprinting of H19 and IGF-2. Because the imprinting pattern of the latter genes differs from that found in testicular GCTs of adult patients, our data suggest that pediatric GCTs arise from a different stage of germ cell development.

Adolescent↗
PubMed2001

[Expression of telomerase subunits and its relationship with telomerase activity in nasopharyngeal carcinoma].

OBJECTIVE: To study the expression of telomerase subunits and its relationship with telomerase activity in nasopharyngeal carcinoma. METHODS: The expression of telomerase subunits and the telomerase activity were examined in the same sample from nasopharyngeal carcinoma (NPC) as well as from chronic inflammation of nasopharyngeal epithelium (CINE) with RT-PCR and PCR-ELISA respectively. RESULTS: (1) hTERT mRNA was expressed in 38 of 43 cases of NPC (88%), and in none of the 16 cases of CINE (0%) (P < 0.05). (2) hTR was expressed in 39 of the 43 cases of NPC (90.7%),and in 14 of the 16 cases of CINE (87.5%) (P < 0.05). TP1 mRNA was expressed in 38 of the 43 cases of NPC (88%), and in 14 of the 16 cases of CINE (87.5%). There was no statistically significant difference between the expression of hTR and TP1 mRNA in NPC and their expression in CINE (P > 0.05). (3) Telomerase activity was detected in 37 of the 43 cases of NPC (86%) and in none of the 16 cases of CINE (0%) (P < 0.05). There was a significant correlation between the expression of hTERT mRNA in NPC and CINE (P < 0.05). No correlation was observed between telomerase activity and the expression of hTR and TP1 mRNA (P > 0.05). (5) No correlation was observed between the clinicopathological features of NPC and CINE (such as clinical stage and lymph node metastasis) and the expression of any of the telomerase subunits (P > 0.05). CONCLUSION: The expression of hTERT may play a critical role in regulation of telomerase activity, and detection of hTERT mRNA might be useful for clinical diagnosis of NPC.

Carcinoma, Squamous Cell↗
PubMed2000

[Expression of telomerase genes in human tumors].

OBJECTIVE: To investigate the correlation between the expression of telomerase genes and malignant phenotypes of human tumors and to compare the expression of telomerase genes and its activity reported in order to evaluate the role of detection of telomerase genes in tumor diagnosis. METHODS: With in situ hybridization, the expression and distribution of telomerase hTR and hTRT genes were observed in 78 cases of human cancer tissues, 20 cases of precancerous lesions and 28 of benign lesions. The results were statistically analyzed. RESULTS: hTR and hTRT were detected in 85% (66/78) and 82% (64/78) of the primary cancers. While in the adjacent tissues, the positive rates were only 3% (2/78) and 5% (4/78). In 20 precancerous cases, the positive rate for hTR and hTRT were 20% (4/20) and 15% (3/20) and the positive cases in 28 benign lesions were 0 and 1/28 (4%), respectively. The positive detection of hTR and hTRT expression in cancer group were significantly different from those in the adjacent tissues, precancerous cases and benign lesion group (P < 0.01). In analysing main types of the human cancers, the positive frequency of hTR and hTRT were 94% (15/16) and 88% (14/16) for the breast cancer, 85% (17/20) and 90% (18/20) for the colon cancer, 80% (8/10) and 80% (8/10) for the gallbladder cancer, 75% (6/8) and 75% (6/8) for the lung cancer, 75% (6/8) and 75% (6/8) for the stomach cancer, and 83% (5/6) and 83% (5/6) for the esophagus cancer, respectively. The expression level of telomerase hTR and hTRT correlated well with the malignancy and metastatic potentials in breast cancer, colon cancer and bladder cancer. Besides, the expressions of hTR and hTRT were noticed to be also highly correlated (P < 0.01). CONCLUSIONS: The expression of telomerase genes correlates with tumor malignant phenotypes, and may reflect the progression of tumors, and the detection of telomerase gene expression may be useful in a retrospective cancer research. It is worthwhile for further study to clarify whether screening of telomerase gene expression is able to become a new index for tumor diagnosis and prognosis.

Breast Neoplasms↗
PubMed2002

The kinetics of deregulation of expression by de novo methylation of the h19 imprinting control region in cancer cells.

Epigenetic lesions are common in neoplasia and range from hypermethylation of subsets of CpG islands to loss of imprinting. By exploiting an episomal model system and the strong de novo methylation capacity of a human cancer cell line, we show that an H19 minigene rapidly becomes methylated and silenced, mimicking the inactivation of the maternal H19 allele in a range of cancers. Although the H19 imprinting control region (ICR) initially displayed methylation protection, it eventually succumbed to the pressure mounted by the de novo methylation machinery of the JEG-3 cells. Importantly, we were able to visualize the kinetics of the loss of the H19 ICR chromatin insulator function in association with chromatin compaction. Our results document that a strong de novo methylation machinery leads to loss of methylation privilege states of H19 ICR to functionally manifest loss of insulator function in a matter of only a few days in human cancer cells.

Animals↗
PubMed2002

Reactivation of a silenced H19 gene in human rhabdomyosarcoma by demethylation of DNA but not by histone hyperacetylation.

BACKGROUND: The active copy of the imprinted gene H19 is turned off by inappropriate methylation in several pediatric tumors including Wilms' Tumour and embryonal rhabdomyosarcoma. H19 controls in cis the linked Insulin-like Growth Factor 2 (IGF2) gene, encoding an important growth factor. Recent work has suggested that methylation of a gene may lead to deacetylation of its associated histones and that silenced genes can be reactivated by increasing histone acetylation levels. RESULTS: Treatment of a rhabdomyosarcoma cell line which has a silent, methylated H19 gene with histone deacetylase (HDAC) inhibitors under conditions which gave maximal hyperacetylation of histone 4, both globally and at the H19 gene itself could not reactivate H19 or affect the active Insulin-like Growth Factor 2 (IGF2) gene, but caused clear up-regulation of the Tissue-type Plasminogen Activator (TPA) gene, a non-imprinted gene known to respond to changes in histone acetylation. In contrast, mild treatment of the cells with the methylation inhibitor 5-AzaC-2'-deoxycytidine (AzaC) on its own was able to reactivate H19. Combining AzaC treatment with HDAC inhibitors gave a reduced rather than enhanced reactivation. These findings were confirmed in mouse primary liver and kidney explants which maintain normal imprinting, where we also found that the silent Igf2 gene could not be reactivated by HDAC inhibitors. CONCLUSION: These results suggest that DNA methylation rather than histone acetylation is the primary determinant of silencing of H19 in rhabdomyosarcoma.

Acetylation↗
PubMedDate not supplied

[Spinocerebellar ataxia type 8: the case of a Spanish family].

INTRODUCTION: Dominant autosomic ataxias include a group of neurodegenerative diseases characterized by the abnormal expansion of triplets. CASE REPORT: Male aged 33, with expansion of the SCA 8 gene (100 repetitions), who presented a clinical picture compatible with a pancerebellar syndrome. The patient had been diagnosed 11 years earlier as suffering from previously of histiocytosis X. A clinico genetic study was conducted on the patient and several members of his family (parents and two sisters). Both sisters and the father were found to be carriers of the expansion (110 and 150 repetitions, respectively), and are currently asymptomatic. RESULTS AND DISCUSSION: There is no relation between the number of repetitions and the age of onset of the disease. The normal interval in our population oscillates between 16 37 repetitions, and the pathological interval has not been well determined. There may be a relation between the SCA 8 form and histiocytosis X.

Adult↗
PubMed2002

Loss of imprinting in colorectal cancer linked to hypomethylation of H19 and IGF2.

Epigenetic alterations in human cancers include global DNA hypomethylation,gene hypomethylation and promoter hypermethylation, and loss of imprinting (LOI) of the insulin-like growth factor-II gene (IGF2). A mechanism for LOI described previously is hypermethylation of a differentially methylated region (DMR) upstream of the H19 gene, allowing activation of the normally silent maternal allele of IGF2. Here we show that this mechanism does not apply to colorectal cancers, which show hypomethylation of the H19 DMR as well as a DMR upstream of exon 3 of IGF2. This hypomethylation is found in both colorectal cancers and normal mucosa from the same patients, and in cell lines with somatic cell knockout of DNA methyltransferases DNMT1 and DNMT3B. These data suggest that hypomethylation is a mechanism for LOI, that the popular IGF2-H19 enhancer competition model for IGF2 imprinting does not apply to the human colon, and that an alternative model for LOI would involve a transcriptional repressor acting on the normally silent maternal allele of IGF2.

Colorectal Neoplasms↗
PubMed2002

Effects of NPC-associated gene NAG7 on cell cycle and apoptosis in nasopharyngeal carcinoma cells.

BACKGROUND & OBJECTIVE: NPC-associated gene NAG7 was a novel candidate tumor suppressor gene associated with nasopharyngeal carcinoma cloned in our laboratory. This study was designed to investigate the potential effect of NAG7 on the cell cycle and apoptosis of nasopharyngeal carcinoma cell line HNE1 and its molecular mechanism. METHODS: NAG7 gene was introduced into HNE1 cells using lipofectin transfection technique. The expression level of NAG7 gene was analyzed by Northern blot. Cell cycle, cyclins, and cell apoptosis were detected by flow cytometry, and the expressions of cyclin D1 and cyclin E were detected by Western blot. RESULTS: NAG7 gene was re-expressed in NAG7 transfected HNE1 cells. Compared with HNE1 cells and vector transfected HNE1 cells, NAG7 transfected HNE1 cells arrested in G0/G1 phase increased (P < 0.05) and cells in S phase decreased (P < 0.05), the apoptosis cells increased (P < 0.05), and the levels of cyclins of A, B1, D1, and E decreased. Furthermore, the expression of cyclin D1 and E decreased in NAG7 transfected HNE1 cells. CONCLUSION: NAG7 gene re-expression could inhibit overproliferation of NPC cell by delaying the progression of G1 into S in cell cycle and inducing cell apoptosis.

Apoptosis↗
PubMed2003

Monoallelic up-regulation of the imprinted H19 gene in airway epithelium of phenotypically normal cigarette smokers.

H19, a paternally imprinted gene, is postulated to have regulatory functions in normal development and oncogenesis. Loss of imprinting (LOI) of H19 is observed in human malignancies, including lung cancer. Microarray assessment of gene expression patterns in airway epithelium of healthy 20 pack-year smokers versus nonsmokers revealed that smokers have dramatically elevated H19 RNA levels without alteration of expression of other imprinted genes. Interestingly, the up-regulation of H19 was not attributable to LOI, i.e., expression of H19 in smokers was monoallelic. These observations suggest that cigarette smoking initially induces up-regulation of the active H19 allele and that there is likely progression to LOI as the burden of smoking increases and as the epithelium undergoes transition from normal to neoplastic. Overexpression and eventual LOI of H19 may represent early markers in the progression of airway epithelium toward lung cancer.

Adult↗