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PubMed1999

Heterochromatin.

The properties of heterochromatin are reconsidered in the context of our present understanding of gene silencing, telomeric and centromeric properties, position-effect variegation and X-chromosome inactivation. It is proposed that the chromatin in heterochromatic chromosomal regions is generally similar in its molecular composition to that in silenced chromosomal regions. Heterochromatic appearance hence reflects not a particular quality of the respective chromosomal regions but only a specific kind of chromatin packaging comparable to that required for the inactivation of genes. This packaging may be initiated by particular signals in the DNA but can be propagated over more extended chromosomal regions by the formation of multiprotein complexes that interact with histones and possibly cell-specific additional components (RNA or proteins) that determine the status of the chromosome in a particular cell type.

Animals↗

PubMed2001

Expression of Xist RNA is sufficient to initiate macrochromatin body formation.

MacroH2A1 is a histone variant that is found as a component of the inactive X chromosome where it is detected as a dense accumulation called a macrochromatin body (MCB). Macrochromatin bodies co-localize with Xist RNA, which is an untranslated RNA that is expressed exclusively from the inactive X chromosome of placental mammals. However, no studies to date have investigated whether Xist RNA expression is necessary or sufficient to cause the formation of MCBs. Here we show that expression of Xist RNA is sufficient to cause the formation of MCBs even when Xist is expressed from an inducible transgene at ectopic autosomal sites. Macrochromatin bodies form at sites of transgenic Xist expression in differentiating mouse ES cell lines and transgenic fibroblasts, but MCBs cannot form in undifferentiated ES cells even after prolonged Xist expression. The kinetics of MCB formation revealed that Xist expression precedes MCB formation and that differentiating ES cells undergo a rapid and synchronous transition that renders them competent to form MCBs. Once MCBs have formed, continued expression of Xist is required for their maintenance. These results show that Xist RNA and macroH2A1 function in a common pathway. Expression of Xist in a permissive nuclear environment is sufficient to initiate a chromatin-remodeling event culminating in the incorporation of macroH2A1. The results also strongly suggest the existence of additional regulatory factors for X inactivation that are regulated developmentally. In addition, we present evidence that macroH2A1 density is not simply a measure of the general degree of DNA compaction.

Animals↗

PubMed2004

A parent-of-origin detectable polymorphism in the hypermethylated region upstream of the human H19 gene.

The H19 gene is a paternally imprinted gene located on chromosome 11p15.5. In this study the H19FR haplotype polymorphism including three SNPs upstream of the H19 gene was investigated. Six genotypes derived from three alleles were detected in the Japanese population by means of PCR and subsequent constant denaturing gel electrophoresis. Based on the methylation status of the genomic DNA from blood samples, selective detection of the parental allele for H19FR was examined by using two types of enzyme, the methylation-sensitive restriction enzymes HpaII or HhaI and McrBC. Genomic DNA digested by either HpaII or HhaI, revealed a single band derived from the paternal allele, as a result of cleavage of unmethylated recognition sites on the maternal allele. On the contrary, the use of McrBC, which can digest a methylated paternal sequence, resulted in exclusively amplifying the maternal allele. This method could be one of the useful techniques for discriminating the parental origin of alleles.

Alleles↗

PubMed2002

Analysis of SCA8 and SCA12 loci in 134 Italian ataxic patients negative for SCA1-3, 6 and 7 CAG expansions.

Spinocerebellar ataxias (SCA) are a heterogeneous group of neurodegenerative disorders, six of which are caused by expansion of a polyglutamine-coding CAG repeats ( SCA1- 3, 6, 7 and 17). In addition, expansions of a CAG triplet in the 5' region of a gene and a CTG triplet in an antisense RNA have been demonstrated in the SCA12 and SCA8 genes respectively. Our series of 134 ataxic patients (22 familial and 112 sporadic, tested negative for SCAI-3, 6, 7) was investigated for the presence of triplet expansions in the SCA8 and SCA12 genes. No SCA12 expansion was identified. A moderate SCA8 expansion (85-97 repeats) was found in two unrelated families with slowly progressive cerebellar ataxia. The frequency of SCA8 expansion accounts for approximately 4.3 % of the whole pool of our ataxia families (2 out of 46), while none of the 127 controls screened carried > 35 CTG+CTA repeats. Our data suggest a possible pathogenetic role of this mutation, which at present is still controversial, and confirm the rarity of the SCA12 expansion in Italian patients.

Adolescent↗

PubMed2005

Correlation of the expression of telomerase RNA with risk factors for recurrence of sebaceous gland carcinoma.

AIMS: To investigate the expression of human telomerase gene RNA (hTR) and human telomerase reverse transcriptase (hTRT) in eyelid sebaceous gland carcinoma and to evaluate risk factors for sebaceous carcinoma recurrence. METHODS: The expression patterns of hTR and hTRT were detected by in situ hybridization (ISH) in paraffin-embedded samples of 55 eyelid sebaceous gland carcinoma, 12 chalazia, and four sebaceous adenoma. The proliferation index (PI) of sebaceous gland carcinoma was determined by Ki-67 immunolabeling and the results were compared with the expression of hTR and hTRT. Several factors for recurrence of sebaceous gland carcinoma were evaluated by statistical analysis. RESULTS: Expression of hTR and hTRT was present mainly in the sebaceous gland carcinoma tissues and not in adjacent tissues of carcinoma, chalazia, and sebaceous adenoma. The prevalence of hTR, hTRT, and Ki-67 expression in 55 sebaceous carcinoma samples were 84.45%, 58.1%, and 78.18%, respectively. hTR expression was highly associated with the degree of carcinoma differentiation (P<0.001) and hTRT expression was correlated with the proliferation index as determined by Ki-67 staining (P<0.005). There was a correlation between the recurrence of sebaceous gland carcinoma and the patient's onset age (OR=0.914, P<0.05), as well as the time to first treatment (OR=1.163, P<0.01). CONCLUSIONS: Telomerase may play an important role in the carcinogenesis of sebaceous gland carcinoma, and expression of hTR and hTRT combined with other features of sebaceous gland carcinoma may be helpful for the diagnosis and evaluation of clinical prognosis. Risk factors for recurrence of sebaceous gland carcinoma are patients' onset age and the time to first treatment.

Adenocarcinoma, Sebaceous↗

PubMed2003

Polycomb-group proteins are involved in silencing processes caused by a transgenic element from the murine imprinted H19/Igf2 region in Drosophila.

A subset of autosomal genes undergo genomic imprinting which results in expression from only the paternal or maternal chromosome. While this phenomenon is restricted to mammals and angiosperms, the underlying silencing mechanisms appear to be evolutionarily conserved. A biallelically unmethylated DNaseI hypersensitive region (A6-A4) between the imprinted Igf2 and H19 genes is conserved in humans and mice and functions as a tissue-specific maintenance element for the imprinted growth factor IGF2. In order to analyse A6-A4 for potentially conserved transcriptional maintenance properties, we have generated transgenic Drosophila harbouring the element in a reporter construct. These flies depicted silencing of the reporter genes lacZ and mini -white. The silenced state of the mini -white gene showed variegation and sensitivity to temperature changes. In addition, two members of the conserved Polycomb group, Enhancer of zeste and Posterior sex combs, were needed for repression. Polycomb group proteins are essential for gene silencing during development. Our results indicate that Polycomb group proteins may also be involved in the regulation of mammalian imprinted genes.

Animals↗

PubMed1998

H19 and Igf2 are expressed and differentially imprinted in neuroectoderm-derived cells in the mouse brain.

Igf2 and H19 are reciprocally imprinted genes that are closely linked and coexpressed in tissues of mesodermal and endodermal origin. Here we report that coexpression of these genes is also found in specific fetal tissues of neuroectodermal origin, that is in the ventral midline region of both the hindbrain and spinal cord. For cells of neuroectodermal origin, complete absence of Igf2 and H19 transcription was previously described. Analysis of allele-specific expression of both Igf2 and H19 in the ventral midline region of the hindbrain shows that H19 is expressed monoallelically, with the paternal allele being silent, whereas Igf2 is expressed biallelically. Furthermore, we observed a strong influence of the parental species background, in that the Mus musculus allele was always expressed at higher levels than the M. spretus allele. This was observed when the M. spretus allele was contributed by the mother or by the father. An analysis of Igf2 methylation by bisulphite genomic sequencing provided no clear answer as to whether Igf2 expression and methylation are linked in a tissue of neuroectodermal origin. Taken together, our results provide novel information on H19 and Igf2 expression and imprinting patterns in the fetal mouse brain. In addition, they indicate that some aspects of Igf2 regulation in cells of neuroectodermal origin do not follow the pattern that exists in mesoderm- and endoderm-derived tissues. Apart from the ventral midline region, H19 and Igf2 were found to be coexpressed in the ectodermally derived Rathke's pouch and in some circumventricular organs of the brain, such as the organum vasculosum of the lamina terminalis (OVLT) and the pineal gland.

Animals↗

PubMed1999

Random monoallelic expression of the imprinted IGF2 and H19 genes in the absence of discriminative parental marks.

The IGF2 and H19 genes are genomically imprinted and expressed preferentially from the paternal and maternal alleles, respectively, during human prenatal development. The exact role of the parental imprint(s), however, is not known. To explore this issue in some detail, we have examined human androgenetic cells which by definition should be incapable of allelic discrimination given the paternal origin of both genomes. Allele-specific in situ hybridisation analysis of dispermic complete hydatidiform moles shows that IGF2 and H19 can be found to be transcriptionally active in a variegated manner, which results in the generation of random monoallelic expression patterns. This data shows that imprinted genes can be expressed monoallelically in the absence of discriminating parental marks and raises the question whether or not mechanisms underlying monoallelic expression preceded the acquisition of parental imprints during evolution.

Alleles↗

PubMed1999

Role of a 461-bp G-rich repetitive element in H19 transgene imprinting.

The molecular mechanism leading to the imprinted expression of genes is poorly understood. While no conserved cis-acting elements have been identified within the known loci, many imprinted genes are located near directly repetitive sequence elements, suggesting that such repeats might play a role in imprinted gene expression. The maternally expressed mouse H19 gene is located approximately 1.5 kb downstream from a 461-bp G-rich repetitive element. We have used a transgenic model to investigate whether this element is essential for H19 imprinting. Previous results demonstrated that a transgene, which contains 14 kb of H19 sequence, exhibits parent-of-origin specific expression and methylation analogous to the endogenous H19 imprinting pattern. Here, we have generated transgenes lacking the G-rich repeat. One transgene, containing a deletion of the G-rich repetitive element but which includes an additional 1.7 kb of 5' H19 sequence, is imprinted similarly to the endogenous H19 gene. To determine whether the G-rich repeat is conserved in other imprinted mammalian H19 homologues, additional 5' flanking sequences were cloned from the rat and human. This element is conserved in the rat but not in human DNA. These results suggest that the 461-bp G-rich repetitive element is not essential for H19 imprinting.

Animals↗

PubMed2000

Analysis of ENOD40 expression in alb1, a symbiotic mutant of Lotus japonicus that forms empty nodules with incompletely developed nodule vascular bundles.

The alb1 mutant of Lotus japonicus (Ljsym74) forms empty nodules in which most of the bacteria remain in abnormally enlarged infection threads and fail to enter the host plant cells. The alb1 mutant was also found to be defective in differentiation of ramified nodule vascular bundles; only a single vascular bundle differentiates at the proximal end of the alb1 nodules and it fails to differentiate further. Histochemical analysis using fluorescein-conjugated wheat-germ agglutinin (F-WGA) indicated that the mutation in the ALB1 gene specifically affects the differentiation of vascular bundles in nodules. Analysis of nodulin gene expression revealed that the expression of an early nodulin gene, ENOD40, was very low in alb1 nodules. At early developmental stages of alb1 nodules, the pattern of ENOD40 transcription was essentially the same as that in wild-type nodules; transcripts were localized in dividing cortical cells and in the pericycle of the root stele opposite nodule primordia, as in wild-type nodules. However, mature alb1 nodules exhibited very weak or no expression of ENOD40 in the peripheral cells of the undeveloped nodule vascular bundle. The ENOD40 expression pattern in alb1 nodules is distinct from that in another ineffective mutant, fen1 (Ljsym76), in which ENOD40 expression persists prior to premature senescence. These findings lead us to speculate that ENOD40 may play a role in the differentiation of nodule vascular bundles.

Fabaceae↗

PubMed2003

Biallelic expression of HRAS and MUCDHL in human and mouse.

At least eight genes clustered in 1 Mb of DNA on human chromosome (Chr) 11p15.5 are subject to parental imprinting, with monoallelic expression in one or more tissues. Orthologues of these genes show conserved linkage and imprinting on distal Chr 7 of mice. The extended imprinted region has a bipartite structure, with at least two differentially methylated DNA elements (DMRs) controlling the imprinting of two sub-domains. We previously described three biallelically expressed genes ( MRPL23, 2G7 and TNNT3) in 100 kb of DNA immediately downstream of the imprinted H19 gene, suggesting that H19 marks one border of the imprinted region. Here we extend this analysis to two additional downstream genes, HRAS and MUCDHL (mu-protocadherin). We find that these genes are biallelically expressed in multiple fetal and adult tissues, both in humans and in mice. The mouse orthologue of a third gene, DUSP8, located between H19 and MUCDHL, is also expressed biallelically. The DMR immediately upstream of H19 frequently shows a net gain of methylation in Wilms tumors, either via Chr 11p15.5 loss of heterozygosity (LOH) or loss of imprinting (LOI), but changes in methylation in CpG-rich sequences upstream and within the MUCDHL gene are rare in these tumors and do not correlate with LOH or LOI. These findings are further evidence for a border of the imprinted region immediately downstream of H19, and the data allow the construction of an imprinting map that includes more than 20 genes, distributed over 3 Mb of DNA on Chr 11p15.5.

Alleles↗

PubMed2000

Seven ring (X) chromosomes lacking the XIST locus, six with an unexpectedly mild phenotype.

Small ring (X) chromosomes lacking the XIST gene at Xq13.2 have been associated with a severe phenotype that includes mental retardation, facial dysmorphism and congenital abnormalities. It has been hypothesised that the loss of XIST results in functional disomy for the sequences contained in the ring. We studied 47 females with a 45,X/46,r(X) karyotype and found seven to have an XIST-negative ring. Only one of the seven patients had the severe phenotype. The remaining six patients had physical phenotypes consistent with Turner syndrome. The rings were characterised cytogenetically and molecularly. The severe phenotype in one patient can be explained by the absence of XIST expression, the relatively large amount of Xp material in the ring and, possibly, the concomitant maternal uniparental isodisomy. We propose three explanations for the unexpectedly mild phenotypes in the remaining six patients; (1) the rings contained limited amounts of X-chromosome material, and sequences that, when functionally disomic, result in a severe phenotype were absent; (2) mosaicism resulting in the absence of the ring from tissues, such as the brain, which are important in the severe phenotype and (3) the presence of an inactive X in some tissues at some time, exemplified by the demonstration of XIST expression in one patient.

Abnormalities, Multiple↗

PubMedDate not supplied

Beckwith-Wiedemann syndrome-associated hepatoblastoma: wnt signal activation occurs later in tumorigenesis in patients with 11p15.5 uniparental disomy.

Beckwith-Wiedemann syndrome (BWS) patients with chromosome 11p15.5 uniparental isodisomy (UPD) have an increased risk for developing embryonal tumors. UPD in these patients involves maternal loss of heterozygosity (LOH) and paternal duplication, which leads to tissue overgrowth and tumor development. Although 11p15.5 UPD predisposes to tumorigenesis, the events leading to tumorigenesis in UPD patients remains unknown. We have examined two hepatoblastomas in the BWS patients with UPD to determine the sequence of genetic events. Constitutional 11p15.5 LOH was detected in the blood or nonneoplastic liver of the BWS patients with hepatoblastoma. Mutation of beta-catenin gene (CTNNB1) was found in one hepatoblastoma. Although mutations in CTNNB1 were not found in the second hepatoblastoma, nuclear accumulation of beta-catenin was detected. However, mutation of CTNNB1 or nuclear accumulation of beta-catenin was not detected in the tissue with hepatomegaly which contains UPD cells. These data indicate that Wnt signal activation can be involved as a later event in BWS-associated hepatoblastoma involving 11p15.5 UPD.

Adaptor Proteins, Signal Transducing↗

PubMedDate not supplied

Nesidioblastosis and mixed hamartoma of the liver in Beckwith-Wiedemann syndrome: case study including analysis of H19 methylation and insulin-like growth factor 2 genotyping and imprinting.

An infant with persistent hyperinsulinemic hypoglycemia, diffuse nesidioblastosis, and mixed hamartoma of the liver (MHL), in addition to demonstrating clinical, pathologic, and molecular manifestations of Beckwith-Wiedemann syndrome (BWS), is the subject of this report. H19 methylation assay and allelic expression analysis for insulin-like growth factor 2 (IGF2) indicated that the patient was mosaic for paternal isodisomic cells and normal cells in lung tissue, nontumoral liver tissue, tissue from the MHL, and pancreatic tissue. We propose that abundant IGF2 expression during development due to paternal isodisomy resulted in hepatomegaly and islet cell hyperplasia, which led to nesidioblastosis. MHL, by contrast, may have resulted from a decrease in disomic cells, compared with nontumoral liver tissue, which showed an increase in disomic cells. Thus, somatic mosaicism may result in unbalanced tissue growth, which may contribute to the formation of MHL in BWS.

Allelic Imbalance↗

PubMed1998

In situ detection of insulin-like growth factor II (IGF2) and H19 gene expression in hepatocellular carcinoma.

To assess the relationship between insulin-like growth factor II (IGF2) and H19 gene expression at the cellular level, we have examined the distribution of IGF2 and H19 mRNA by means of an situ hybridization in hepatic malignancies consisting of hepatocellular carcinoma (HCC), cholangiocellular carcinoma (CCC), and metastatic liver cancer (MLC). In HCC, 15 of 27 tumors (56%) and 11 of 27 tumors (41%) demonstrated increased IGF2 and H19 gene expression, respectively. Of 16 HCCs with increased expression of either IGF2 or H19, 10 tumors coexpressed both transcripts at comparable levels. Moreover, the spatiotemporal distribution and the cellular localization of the two gene transcripts were almost identical, suggesting the presence of a reciprocal relation between IGF2 and H19. In addition, 5 HCCs showed increased IGF2 expression without concomitant H19 expression, whereas 1 HCC showed increased H19 expression without IGF2 transcripts. However, 11 HCCs showed no IGF2 or H19 expression. On the other hand, neither IGF2 transcripts nor H19 transcripts were detected in 2 CCCs or 10 MLCs studied. The data suggest that IGF2 and/or H19 gene expression may be characteristic of some HCCs.

Adolescent↗

PubMed1999

Repeat-directed isolation of a novel gene preferentially expressed from the maternal allele in human placenta.

Using a repetitive sequence of tandemly arrayed pentanucleotides in the human H19 3'-flanking region, we isolated a phage clone (lambda PEN11) which localized to chromosome 11p15.5. The lambda PEN11 phage encodes a 2.3-kb cDNA consisting of seven exons at least. The gene was mainly expressed in brain and pancreas (and less abundantly in testis), and demonstrated differential allele usage, with maternal expression being predominant in placenta, which indicates the gene is an atypical imprinted gene. While the pentamer repeat might contribute to this effect, it is also possible that the differential allele usage might reflect the local chromosomal structure known as the imprinting domain.

Alleles↗

PubMed2005

Brief report: non-random X chromosome inactivation in females with autism.

Autism is a heterogeneous neurodevelopmental disorder with a 3-4 times higher sex ratio in males than females. X chromosome genes may contribute to this higher sex ratio through unusual skewing of X chromosome inactivation. We studied X chromosome skewness in 30 females with classical autism and 35 similarly aged unaffected female siblings as controls using the polymorphic androgen receptor (AR) gene. Significantly, increased X chromosome skewness (e.g., >80:20%) was detected in our autism group (33%) compared to unaffected females (11%). X chromosome skewness was also seen in 50% of the mothers with autistic daughters. No mutation was seen in the promoter region of the XIST gene reported to be involved in X chromosome inactivation in our subjects. X chromosome skewness has been reported in female carriers of other neurological disorders such as X-linked mental retardation, adrenoleukodystrophy and Rett syndrome.

Autistic Disorder↗

PubMed2003

Anticipation and CAG*CTG repeat expansion in schizophrenia and bipolar affective disorder.

The genetic contribution to the etiologies of schizophrenia and bipolar affective disorder (BPAD) has been considered for many decades, with twin, family, and adoption studies indicating consistently that the familial clustering of affected individuals is accounted for mainly by genetic factors. Despite the strong evidence for a genetic component, very little is understood about the underlying genetic and molecular mechanisms for schizophrenia and BPAD. In the early 1990s, after the discovery of "dynamic mutation" or "unstable DNA" as a molecular basis for the genetic anticipation observed in Huntington's disease, myotonic dystrophy, and many others, and the recently rediscovered, albeit still controversial, evidence for genetic anticipation in major psychoses, the genetic epidemiology of schizophrenia and BPAD was re-evaluated to demonstrate strong endorsement for the unstable DNA model. Many of the non-Mendelian genetic features of schizophrenia and BPAD could be explained by the behaviour of unstable DNA, and several molecular genetic approaches became available for testing the unstable DNA hypothesis. However, despite promising findings in the mid-1990s, no trinucleotide repeat expansion has yet been identified as a cause of idiopathic schizophrenia or BPAD.

Bipolar Disorder↗