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PubMed1997

Allelic and interlocus comparison of the PERB11 multigene family in the MHC.

The major histocompatibility complex (MHC) contains at least a hundred genes over 4 megabases of DNA. Within the MHC there are several new multigene families which have been recently described. PERB11 is a multigene family which occurs over the class I and central region of the MHC. Two members of the family have been shown to be functional and share domains with members of the supergene family including HLA class I, FcRn, and Zn-alpha2-glycoprotein molecules. The two functional members are contained within an area of the MHC which has been associated with increased susceptibility to autoimmune diseases such as insulin-dependent diabetes mellitus and also rapid progression to AIDS following HIV-1 infection. Intralocus and interlocus differences between PERB11.1 and PERB11.2 include: (1) several nucleotide substitutions leading to amino acid changes; (2) presence and absence of potential glycosylation sites; (3) insertions and deletions leading to a frame shift resulting in diversity at the amino acid level and an early termination signal. There are ten different alleles of PERB11.1 including one allele which contains a frame shift in the transmembrane region causing a putative truncated molecule lacking the cytoplasmic tail. The significance of this polymorphism in disease associations is under investigation. The most divergent domain is the transmembrane region when PERB11.1 and PERB11.2 are compared. The results suggest that these two molecules may have different functions.

Alleles↗
PubMed1999

The P5 multicopy gene family in the MHC is related in sequence to human endogenous retroviruses HERV-L and HERV-16.

P5 is believed to be a multicopy gene family with at least eight members restricted to the major histocompatibility complex (MHC). Although the function of P5 genes is not known, one of the family members, P5-1, was found previously to be specifically transcribed in lymphoid cells and tissue. In this study, we used computer programs Censor and RepeatMasker, and dot plot analysis to show that the major P5 family members are related in sequence to human endogenous retroviruses, HERV-L and HERV-16. The P5-HERV sequences have at least 60% sequence identity with HERV-L within the pol region but differ significantly within the gag and LTR regions. The LTRs flanking the P5-HERV sequences share about 70% identity with the repeat element LTR16B. Structural analysis of open reading frames (ORFs) confirmed that the P5-1 cDNA is characterized by many stop codons and short putative coding regions resembling the patterns found in the HERV-L nucleotide sequence rather than those found in an mRNA sequence such as expressed by HLA class I genes. A 159 base pair (bp) ORF at the 5' end of the 2535 bp P5-1 mRNA may code for a peptide of 52 amino acids with a domain identical in sequence to the signal peptide of HLA molecules. Furthermore, the P5-1 mRNA is complementary in sequence to retroviral pol mRNA. Therefore, the P5-1 genomic sequence appears to be an example of an HERV within the MHC that expresses an antisense transcript with a possible role in immunity to retrovirus infection.

Amino Acid Sequence↗
PubMed2001

Infection of synoviocytes with HTLV-I induces telomerase activity.

To investigate the mechanism of synovial hyperplasia by human T-lymphotropic virus type I (HTLV-I) infection, the enzymatic activity of telomerase and expression of telomerase-related factors in HTLV-I infected synoviocytes were examined. Cultured synoviocytes obtained from four patients with osteoarthritis (OA) and four with traumatic joint disease (TJD) were infected by HTLV-I. Telomerase activity was detected by telomeric repeat amplification protocol (TRAP) assay. Expression of telomerase-related mRNAs such as telomerase reverse transcriptase (hTERT), telomerase RNA component (hTERC), and telomeric repeat binding factor 2 (TRF2) were also examined. Telomerase activity was detected in all HTLV-I-infected synoviocytes but not in uninfected synoviocytes. A remarkable induction of hTERT mRNA was observed in four of eight HTLV-I-infected synoviocytes, whereas expressions of hTERC, TRF2, and TEP-1 mRNAs were not changed. Our results clearly demonstrate that HTLV-I upregulates telomerase activity in synoviocytes probably via upregulation of hTERT activity. These findings suggest that telomerase activation in synoviocytes has an important role in upregulated proliferative activity of HAAP synoviocytes.

Carrier Proteins↗
PubMed2000

A revision of the human XIST gene organization and structural comparison with mouse Xist.

The XIST gene plays an essential role in X Chromosome (Chr) inactivation during the early development of female humans. It is believed that the XIST gene, not encoding a protein, functions as an RNA. The XIST cDNA is unusually long, as its full length is reported to be 16.5 kilobase pairs (kb). Here, comparison of sequences from the genomic interval downstream to the 3' end of the human XIST gene against the human EST database brought to light a number of human EST sequences that are mapped to the region. Furthermore, PCR amplification of human cDNA libraries and RNA fluorescence in situ hybridization (RNA-FISH) demonstrate that the human XIST gene has additional 2.8 kb downstream sequences which have not been documented as a part of the gene. These data show that the full-length XIST cDNA is, in fact, 19.3 kb, not 16.5 kb as previously reported. The newly defined region contains an intron that may be alternatively spliced and seven polyadenylation signal sequences. Sequences in the newly defined region show overall sequence similarity with the 3' terminal region of mouse Xist, and three subregions exhibit quite high sequence conservation. Interestingly, the new intron spans the first two sub-regions that are absent in one of the two isoforms of mouse Xist. Taken together, we revise the structure of human XIST cDNA and compare cDNA structures between human and mouse XIST/Xist. al. 1992). This gene, called XIST/Xist (X inactive specific transcript), shows several interesting features. First, both human and mouse XIST/Xist cDNA are unusually long, reportedly 16.5 kb and 17.8 kb, respectively (Brown et al. 1992; Hong et al. 1999). Second, the transcript does not seem to encode a protein, on the basis of the lack of a significant open reading frame, absence of the Xist RNA from polysomes, and localization of the transcript in the nucleus (Brockdorff et al. 1992; Brown et al. 1992). Third, the XIST/Xist RNA physically associates with, or 'coats,' the inactive X Chr (Brown et al. 1992; Clemson et al. 1996). Fourth, XIST/Xist transcripts can be observed as early as the four-cell stage, and upon the initiation of X-inactivation, the steady-state level of the transcript rises dramatically, apparently by stabilization of the RNA (Panning et al. 1997; Sheardown et al. 1997). Although the function of XIST/Xist is not known, deletion of the gene leads to failure of X-inactivation, and knock-out mice die around the gastrulation stage (Marahrens et al. 1997; Penny et al. 1996). In this report, we revise the structure of the human XIST cDNA and discuss structural features of the newly defined region.

Animals↗
PubMed1997

Matrix-attachment regions in the mouse chromosome 7F imprinted domain.

We have mapped the matrix-attachment regions (MARs) in 200 kilobases of the mouse Chromosome (Chr) 7F imprinted domain. MARs are genetic elements known to have effects in cis on methylation at nonimprinted loci. The imprinting of the Igf2 and Ins2 genes is dependent on the transcription of the downstream H19 gene. The transcription of H19 is dependent in turn on its methylation status. The cis-acting regulators of methylation at this site are not known. As MARs are potential regulators not only of methylation but also other elements of genomic imprinting, we mapped the MARs within the 200 kilobases around H19. This report describes the mapping of four MARs from this region.

Animals↗
PubMed1998

Genomic imprinting in ruminants: allele-specific gene expression in parthenogenetic sheep.

Studies in the mouse have established that both parental genomes are essential for normal embryonic development. Parthenogenetic mouse embryos (which have two maternal genomes and no paternal genome), for example, are growth-retarded and die at early postimplantation stages. The distinct maternal and paternal contributions are mediated by genomic imprinting, an epigenetic mechanism by which the expression of certain genes is dependent on whether they are inherited from mother or father. Although comparative studies have established that many imprinted mouse (and rat) genes are allele-specifically expressed in humans as well (and vice versa), so far imprinting studies have not been performed in other mammalian species. When considering evolutionary theories of genomic imprinting, it would be important to know how widely it is conserved among placental mammals. We have investigated its conservation in a bovid ruminant, the domestic sheep, by comparing parthenogenetic and normal control embryos. Our study establishes that, like in the mouse, parthenogenetic development in sheep is associated with growth-retardation and does not proceed beyond early fetal stages. These developmental abnormalities are most likely caused by imprinted genes. We demonstrate that, indeed, like in mice and humans, the growth-related PEG1/MEST and Insulin-like Growth Factor 2 (IGF2) genes are expressed from the paternal chromosome in sheep. These observations suggest that genomic imprinting is conserved in a third, evolutionarily rather diverged group of placental mammals, the ruminants.

Alleles↗
PubMed1999

Compact chromatin packaging of inactive X chromosome involves the actively transcribed Xist gene.

The Xist gene responsible for X inactivation may take a unique chromatin structure because of exceptional expression from inactive X Chromosome, (Chr). We have examined differential chromatin packaging of the Xist gene region between active and inactive X Chr with a novel method consisting of the chromatin fractionation and allele-specific detection. Analysis of F1 heterozygous female mice from T(X;16)16H x MSM crosses and two cell clones derived from inter-subspecific F1 female mice demonstrated that the packaging level of the transcribed Xist region on inactive X Chr was as tight as that of the repressed Pgk-1 allele on the same chromosome. On the other hand, restriction endonuclease sensitivity assay of chromatin showed that the promoter region, but not transcribed regions, of the transcribed Xist allele retained accessibility to nucleases. These results may suggest a cis-element(s) in a regulatory region of the Xist gene to prevent the transcriptionally inhibitory effect of the chromatin packaging.

Animals↗
PubMed1997

Xist RNA is associated with the transcriptionally inactive XY body in mammalian male meiosis.

In eutherian mammals, X inactive-specific transcripts (Xist) are expressed in somatic cells possessing more than one X chromosome, and in germline cells of males, in which the single X chromosome is transcriptionally inactive. In early meiosis of males the sex chromosomes form an inactive XY nuclear compartment (XY body). We show by in situ reverse-transcribed polymerase chain reaction that Xist RNA is concentrated in the XY body. This fine localization suggests that Xist RNA is involved in inactivation of the male X chromosome, and that it has spreading capability, not only in cis but also in a quasi-cis mode, to juxtaposed non-X chromosomes. A hypothetical scheme links the evolution of heteromorphic sex chromosomes to the development of X condensation/inactivation in the male. The mechanism of X inactivation in somatic cells of mammalian females, resulting in male/female dosage compensation, has been recruited from the Xist-activated chromosome condensation machinery that developed in male meiosis earlier in evolution.

Animals↗
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↗
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↗
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↗