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At least 181 records · Page 10Linked to original sources
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

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↗
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↗
PubMed1978

Management of hypercholesterolemia: evaluation of practical clinical approaches in healthy young adults.

A work site-located clinic screened 6,000 employees (91 percent participation) and identified 146 hypercholesterolemic subjects (100 percent initial participation, 12 percent subsequent dropout rate). The subjects, aged 20 to 50 years, were randomly classified into four groups: Group A, treatment in a lipid intervention clinic with diet for 6 weeks, then diet plus clofibrate for the subsequent 18 weeks; Group B, diet treatment from a clinic nutritionist with the cooperation of the subject's private physician; Group C, referral for treatment by a private physician; and Group D, no intervention. Initial mean cholesterol was 294 mg/100 ml. At 24 weeks, all intervention groups had decreases in serum cholesterol (Group A, 12 percent; Group B, 15 percent; Group C, 17 percent; P less than 0.001). The control group (D) had a small decrease in cholesterol (4 percent). Decreases in cholesterol were correlated with weight loss and decrease in fasting serum triglycerides but not with the use of clofibrate. Serum cholesterol can be reduced in healthy young adults by several practical methods.

Adult↗
PubMed1992

Developmental change in subcellular location of Bp-1 protein with an ability to interact with both identifier sequence and its brain-specific transcript, BC-1 RNA.

Identifier sequences are transcribed to generate a brain-specific BC-1 RNA present as a ribonucleoprotein particle in the dendrites and somata of neurons. This ribonucleoprotein particle contains an identifier sequence-binding protein (Bp-1 protein). We report here the purification of BC-1 RNA and demonstrate that Bp-1 protein interacts directly with the RNA. We also demonstrate an accumulation of Bp-1 protein in the nucleus of brain cells from mouse fetus and newborns that precedes the postnatal increase in BC-1 RNA. Cytoplasmic Bp-1 protein present in a complex with BC-1 RNA increases postnatally with a concomitant decrease in nuclear Bp-1 protein. These observations suggest that Bp-1 protein may play a role(s) in the synthesis and nuclear export of BC-1 RNA.

Aging↗
PubMed1995

The expression of the imprinted H19 and IGF-2 genes in human bladder carcinoma.

The imprinted H19 gene is highly expressed in human embryos, fetal tissues and is nearly completely shut off in adults. However, it is reexpressed in a number of tumors including bladder carcinoma, demonstrating that H19 RNA is an oncofetal RNA. Tumors induced by injection of bladder carcinoma cell lines express H19 in contrast to the cells before injection. These observations support the notion of a positive correlation between H19 expression and bladder carcinoma. Loss of imprinting of H19 and IGF-2 was observed in samples of human bladder carcinoma.

Animals↗
PubMed1992

The product of the mouse Xist gene is a 15 kb inactive X-specific transcript containing no conserved ORF and located in the nucleus.

The Xist gene maps to the X inactivation center region in both mouse and human, and previous analysis of the 3' end of the gene has demonstrated inactive X-specific expression, suggesting a possible role in X inactivation. We have now analyzed the entire mouse Xist gene. The mature inactive X-specific transcript is 15 kb in length and contains no conserved ORF. The Xist sequence contains a number of regions comprised of tandem repeats. Comparison with the human XIST gene demonstrates significant conservation of sequence and gene structure. Xist RNA is not associated with the translational machinery of the cell and is located almost exclusively in the nucleus. Together with conservation of inactive X-specific expression, these findings support a role for Xist in X inactivation, possibly as a functional RNA or as a chromatin organizer region.

Animals↗
PubMed1992

The human XIST gene: analysis of a 17 kb inactive X-specific RNA that contains conserved repeats and is highly localized within the nucleus.

X chromosome inactivation in mammalian females results in the cis-limited transcriptional inactivity of most of the genes on one X chromosome. The XIST gene is unique among X-linked genes in being expressed exclusively from the inactive X chromosome. Human XIST cDNAs containing at least eight exons and totaling 17 kb have been isolated and sequenced within the region on the X chromosome known to contain the X inactivation center. The XIST gene includes several tandem repeats, the most 5' of which are evolutionarily conserved. The gene does not contain any significant conserved ORFs and thus does not appear to encode a protein, suggesting that XIST may function as a structural RNA within the nucleus. Consistent with this, fluorescence in situ hybridization experiments demonstrate localization of XIST RNA within the nucleus to a position indistinguishable from the X inactivation-associated Barr body.

Base Sequence↗
PubMed1994

Evidence that random and imprinted Xist expression is controlled by preemptive methylation.

The mouse Xist gene is expressed exclusively from the inactive X chromosome and may control the initiation of X inactivation. We show that in somatic tissues the 5' end of the silent Xist allele on the active X chromosome is fully methylated, while the expressed allele on the inactive X is completely unmethylated. In tissues that undergo imprinted paternal Xist expression and imprinted X inactivation, the paternal Xist allele is unmethylated, and the silent maternal allele is fully methylated. In the male germline, a developmentally regulated demethylation of Xist occurs at the onset of meiosis and is retained in mature spermatozoa. This may be the cause of imprinted expression of the paternal Xist allele. A role for methylation in the control of Xist expression is further supported by the finding that in differentiating embryonic stem cells during the initiation of X inactivation, differential methylation of Xist alleles precedes the onset of Xist expression.

Animals↗
PubMed1996

X chromosome imprinting and inactivation in the early mammalian embryo.

Quantitative differences in X-linked gene expression between androgenetic (two paternal genomes), gynogenetic (two maternal genomes) and normal embryos provide clues into the roles of genomic imprinting and the X:autosome ratio in controlling X chromosome function during development. These data and many others can be accounted for by a new model of X-chromosome-inactivation (XCI). Expression of the Xist RNA from all paternal X chromosomes during development preimplantation leads to repression of genes near the X-chromosome-inactivation center (Xic). Other genes are repressed as a result of spreading of the inactivation, but only in embryos with at least two X chromosomes. XY androgenones are only deficient in expression of genes near the Xic and can form blastocysts, whereas XX androgenones completely inactivate both X chromosomes and die before the blastocyst stage. The X:autosome ratio regulates XCI solely by promoting the spread of inactivation away from the Xic on chromosomes that express Xist. Methylation of the maternal Xist gene is retained in extraembryonic tissues, so that gynogenones and parthenogenones cannot express Xist, do not undergo XCI in those tissues, and so have extraembryonic defects. This model should be relevant to understanding how aberrant X chromosome regulation might occur and how this might contribute to distortion of the X-chromosome-transmission ratio, sex ratio distortion, and disease.

Animals↗
PubMed1995

The H19 gene is expressed within both epithelial and stromal components of human invasive adenocarcinomas.

In a previous work, we have isolated the human H19 gene and shown accumulation of transcripts in various human tumors including breast carcinomas (Douc-Rasy et al (1993) Int J Oncol 2, 753-758). Questions arose, after Northern blot results, about the precise H19 mRNA location, specially in normal breast tissues and benign or malign primary breast tumors. Then we performed molecular in situ hybridization to get insight into tissue expression of the H19 gene. Examined resections included one normal tissue, one fibroadenoma and 13 cancers. Results obtained with the H19 probe can be summarized as follows: 1) in normal breast tissues signals were focally observed in epithelial cells, but more predominantly in the palleal tissue which is sensitive to hormones; 2) in the fibroadenoma, fibroblastic cells were extensively labeled at the stroma-epithelium boundary, but epithelial cells were negative; and 3) in primary cancers, eight specimens exhibited signals on stromal cells, one specimen on epithelial cells and four on both epithelial and stromal cells. Data provide the following evidence: 1) usually labeled cells are clustered, either within normal or pathological tissues; 2) the labeling pattern highly differs from one tumor to another; and 3) H19 probe displays very different signals from one cell to another in given compartment of a given tissue section. In conclusion, it seems that a high H19 expression matches the tumor invasion. Our results suggest that the expression of this gene is concerned by the relationships between epithelial and stromal cells, and can reflect peculiar physiological states of the cells. Furthermore, we discuss results showing an abundant expression of H19 gene in some adenocarcinomas of bad prognosis, in the context of the otherwise established tumor-suppressor role of this gene, or the strictly controlled gene dosage, which could be overridden in these particular cases.

Adenocarcinoma↗
PubMed1996

Neural BC1 RNA in mouse skeletal muscle is a denervation-induced RNA whose expression is developmentally regulated.

We detected neural BC1 RNA in mouse skeletal muscle. The level of BC1 RNA was high in the fetus, but it declined progressively to the adult level as development proceeded. These observations suggest that this RNA is involved in the prenatal development and differentiation of muscles. Although its developmental expression correlates with the fetal period of polyneuronal innervation, BC1 RNA does not seem to play a direct role(s) in synaptogenesis, since its expression was not restricted to the neuromuscular junction. We also demonstrated that the BC1 RNA level in adult muscle was elevated after denervation, suggesting that changes in the activity of muscles or neural factors caused by axotomy, or both may result in BC1 RNA upregulation.

Actins↗