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1.
Three genes on 11p15.5 are known to undergo genomic imprinting. The gene
for insulin-like growth factor II (IGF2) is normally expressed from the
paternal allele, while H19 and p57KIP2, a cyclin-dependent kinase
inhibitor, are expressed from the maternal allele. Five germline balanced
chromosomal rearrangement breakpoints from patients with Beckwith-Wiedemann
syndrome (BWS) have been mapped to 11p15.5 between p57KIP2 and IGF2, and
all are derived from the maternal chromosome. By positional cloning from
BWS breakpoints, we have isolated a gene 100 kb and 65 kb centromeric to
the proximal end of this BWS breakpoint cluster and p57KIP2, respectively.
This gene is homologous to yeast nucleosome assembly protein (NAP1) and to
a human homologue of NAP1, and we designate it hNAP2 (human nucleosome
assembly protein 2). hNAP2 diverges in its expression pattern from IGF2,
H19, and p57KIP2, and it shows biallelic expression in all tissues tested.
Thus, hNAP2 is functionally insulated from the imprinting domain of 11p15.
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2.
Complex phenotypes and genotypes characterize the human disease, Beckwith--Wiedemann syndrome (BWS). Genetic and epigenetic mutations are found in five different genes which all lie within a 1 Mb imprinted domain on human chromosome 11p15. Only two of these genes, p57(KIP2) (CDKN1C) and IGF2, are likely to be functionally involved in this disease. The presence of the additional mutations therefore suggests a role for the regulation of these two genes by distant cis-elements. The mouse Igf2 gene is regulated by enhancers and imprinting elements which lie >120 kb downstream of its promoter. Here we show that key elements for expression of the mouse p57(Kip2) (Cdkn1c) gene also lie at a distance. Enhancers for expression within skeletal muscle and cartilage lie >25 kb downstream of the gene. In addition, we find no evidence for allele-specific expression of p57(Kip2) (Cdkn1c) from our bacterial artificial chromosome transgenes that span 315 kb around the locus. This suggests that a key imprinting element for p57(Kip2) (Cdkn1c) also lies at a distance. Therefore, BWS in humans may result from disruption of appropriate expression of the p57(KIP2) (CDKN1C) gene through mutations that occur at a substantial distance from the gene. 相似文献
3.
Retention of imprinting of the human apoptosis-related gene TSSC3 in human brain tumors 总被引:3,自引:0,他引:3
Müller S van den Boom D Zirkel D Köster H Berthold F Schwab M Westphal M Zumkeller W 《Human molecular genetics》2000,9(5):757-763
Genomic imprinting is the result of a gamete-specific modification leading to parental origin-specific gene expression in somatic cells of the offspring. Several embryonal tumors show loss of imprinting of genes clustered in human chromosome 11p15.5, an important tumor suppressor gene region, harboring several normally imprinted genes. TSSC3, a gene homologous to mouse TDAG51, implicated in Fas-mediated apoptosis, is also located in this region between hNAP2 and p57 (KIP2). TSSC3 is the first apoptosis-related gene found to be imprinted in placenta, liver and fetal tissues where it is expressed from the maternal allele in normal human development. This study investigated the imprinting status of TSSC3 in human normal, adult brain and in human neuroblastomas, medulloblastomas and glioblastomas. A polymorphism in exon 1 at position 54 was used to analyze the allelic expression of the TSSC3 gene by a primer oligo base extension (PROBE) assay using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). We found that the TSSC3 gene is not imprinted in human normal, adult brain and blood. In contrast, strong allelic bias resembling imprinting could be detected in most examined tumor specimens. The results demonstrate for the first time that the tumors under investigation are associated with a retention of imprinting of a potential growth inhibitory gene. 相似文献
4.
IMPT1, an imprinted gene similar to polyspecific transporter and multi- drug resistance genes 总被引:5,自引:1,他引:5
Dao D; Frank D; Qian N; O'Keefe D; Vosatka RJ; Walsh CP; Tycko B 《Human molecular genetics》1998,7(4):597-608
Human chromosome 11p15.5 and distal mouse chromosome 7 include a
megabase-scale chromosomal domain with multiple genes subject to parental
imprinting. Here we describe mouse and human versions of a novel imprinted
gene, IMPT1 , which lies between IPL and p57 KIP2 and which encodes a
predicted multi-membrane-spanning protein similar to bacterial and
eukaryotic polyspecific metabolite transporter and multi- drug resistance
pumps. Mouse Impt1 and human IMPT1 mRNAs are highly expressed in tissues
with metabolite transport functions, including liver, kidney, intestine,
extra-embryonic membranes and placenta, and there is strongly preferential
expression of the maternal allele in various mouse tissues at fetal stages.
In post-natal tissues there is persistent expression, but the allelic bias
attenuates. An allelic expression bias is also observed in human fetal and
post-natal tissues, but there is significant interindividual variation and
rare somatic allele switching. The fact that Impt1 is relatively repressed
on the paternal allele, together with data from other imprinted genes,
allows a statistical conclusion that the primary effect of human chromosome
11p15.5/mouse distal chromosome 7 imprinting is domain-wide relative
repression of genes on the paternal homolog. Dosage regulation of the
metabolite transporter gene(s) by imprinting might regulate placental and
fetal growth.
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5.
Hatada I; Inazawa J; Abe T; Nakayama M; Kaneko Y; Jinno Y; Niikawa N; Ohashi H; Fukushima Y; Iida K; Yutani C; Takahashi S; Chiba Y; Ohishi S; Mukai T 《Human molecular genetics》1996,5(6):783-788
p57KIP2 is a potent tight-binding inhibitor of several G1 cyclin complexes,
and is a negative regulator of cell proliferation. The gene encoding human
p57KIP2 is located on chromosome 11p15.5, a region implicated in both
sporadic cancers and Beckwith-Wiedemann syndrome (BWS), a cancer syndrome,
making it a tumor suppressor candidate. Several types of childhood tumors
including Wilms' tumor, adrenocortical carcinoma and rhabdomyosarcoma
display a specific loss of maternal 11p15 alleles, suggesting that genomic
imprinting plays an important part. Genetic analysis of the familial BWS
has indicated maternal carriers and suggested a role in genomic imprinting.
Previously, we demonstrated that p57KIP2 is imprinted in the mouse. Here we
describe the genomic imprinting of human p57KIP2 and the reduction of its
expression in Wilms' tumors. High resolution mapping locates p57KIP2 in the
region responsible for both tumor suppressivity and BWS.
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6.
Chromosome 11p15.5 regional imprinting: comparative analysis of KIP2 and H19 in human tissues and Wilms' tumors 总被引:9,自引:1,他引:9
The imprinted H19 gene is frequently inactivated in Wilms' tumors (WTs)
either by chromosome 11p15.5 loss of heterozygosity (LOH) or by
hypermethylation of the maternal allele and it is possible that there might
be coordinate disruption of imprinting of multiple 11p15.5 genes in these
tumors. To test this we have characterized total and allele- specific mRNA
expression levels and DNA methylation of the 11p15.5 KIP2 gene in normal
human tissues, WTs and embryonal rhabdomyosarcoma (RMS). Both KIP2 alleles
are expressed but there is a bias with the maternal allele contributing
70-90% of mRNA. Tumors with LOH show moderate to marked reductions in KIP2
mRNA relative to control tissues and residual mRNA expression is from the
imprinted paternal allele. Among WTs without LOH most cases with H19
inactivation also have reduced KIP2 expression and most cases with
persistent H19 expression have high levels of KIP2 mRNA. In contrast to the
extensive hypermethylation of the imprinted H19 allele, both KIP2 alleles
are hypomethylated and WTs with biallelic H19 hypermethylation lack
comparable hypermethylation of KIP2 DNA. 5-aza-2'-deoxycytidine (aza-C)
increases H19 expression in RD RMS cells but does not activate KIP2
expression. These data indicate coordinately reduced expression of two
linked paternally imprinted genes in most WTs and also suggest mechanistic
differences in the maintenance of imprinting at these two loci.
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7.
An extended region of biallelic gene expression and rodent-human synteny downstream of the imprinted H19 gene on chromosome 11p15.5 总被引:1,自引:0,他引:1
There is increasing evidence for chromosomal domains containing multiple
imprinted genes and for domain-wide disruption of imprinting in certain
diseases. In a majority of Wilms' tumors (WTs) there is an abnormal
bipaternal pattern of expression at three imprinted loci, H19, IGF2 and
KIP2, clustered on chromosome 11p15.5. We previously described biallelic
expression of L23MRP, 40 kb downstream of H19. Here we map two additional
genes, the first encoding a ubiquitously expressed RNA, 2G7, and the second
encoding the fast isoform of skeletal muscle troponin-T (TNNT3), in the 55
kb of DNA downstream of L23MRP. 2G7 RNA is spliced and polyadenylated but
lacks long open reading frames. 2G7 and TNNT3 are biallelically expressed
in mid-fetal and adult human tissues and 2G7 shows persistent expression in
WTs. The rat homologue of L23MRP is highly conserved and lies within 85 kb
of H19 in a region of rat chromosome 1 which also contains IGF2 and TNNT3.
Parallel expression of H19 and TNNT3 in different adult skeletal muscle
types suggests that these genes may share an enhancer. These data outline
multiple contiguous loci downstream of H19 which escape functional
imprinting in humans. The rodent-human synteny of this region may
facilitate a search for an imprinting domain boundary.
相似文献
8.
9.
The IPL gene on chromosome 11p15.5 is imprinted in humans and mice and is similar to TDAG51, implicated in Fas expression and apoptosis 总被引:4,自引:1,他引:4
Qian N; Frank D; O'Keefe D; Dao D; Zhao L; Yuan L; Wang Q; Keating M; Walsh C; Tycko B 《Human molecular genetics》1997,6(12):2021-2029
We searched for novel imprinted genes in a region of human chromosome
11p15.5, which contains several known imprinted genes. Here we describe the
cloning and characterization of the IPL ( I mprinted in P lacenta and L
iver) gene, which shows tissue-specific expression and functional
imprinting, with the maternal allele active and the paternal allele
relatively inactive, in many human and mouse tissues. Human IPL is highly
expressed in placenta and shows low but detectable expression in fetal and
adult liver and lung. Mouse Ipl maps to the region of chromosome 7 which is
syntenic with human 11p15.5 and this gene is expressed in placenta and at
higher levels in extraembryonic membranes (yolk sac), fetal liver and adult
kidney. Mouse and human IPL show sequence similarity to TDAG51 , a gene
which was shown to be essential for Fas expression and susceptibility to
apoptosis in a T lymphocyte cell line. Like several other imprinted genes,
mouse and human IPL genes are small and contain small introns. These data
expand the repertoire of known imprinted genes and will be helpful in
testing the mechanism of genomic imprinting and the role of imprinted genes
in growth regulation.
相似文献
10.
11.
Parent-specific expression of a human keratin 18/beta-galactosidase fusion gene in transgenic mice. 总被引:1,自引:0,他引:1
Insertion of a human keratin 18 (K18)-bacterial beta-galactosidase (LacZ) fusion gene into mice has led to a unique transgenic line in which expression of the transgene is subject to unusual germ line-specific, genomic imprinting effects. Fetal expression of the LacZ reporter gene depends on the gender of the transmitting parent, with appropriate expression in liver after maternal inheritance, and ectopic expression in retina and mesodermal tissues after paternal inheritance. This tissue-specific imprinting pattern is superimposed upon a basic expression pattern which is unaffected by parental inheritance. Insertion of the transgene has led to a recessive-lethal phenotype, with no parent-of-origin effects on viability, suggesting that the transgene has not inserted into an imprinted region of the genome. HpaII and HhaI methylation sensitive restriction sites within the bacterial LacZ reporter gene are completely methylated when activity of the maternally inherited transgene is detected in the fetal liver, and not methylated when the paternally inherited transgene is silent. Thus DNA methylation of LacZ is correlated with maternal inheritance and may be implicated in the genomic imprinting mechanism as others have suggested. However, in contrast to the commonly found correlation of expression and low DNA methylation, the LacZ gene was expressed in fetal liver when fully methylated. This result may imply the existence of negative regulatory activities that recognize the unmethylated LacZ gene. 相似文献
12.
p57(KIP2) is not mutated in hepatoblastoma but shows increased transcriptional activity in a comparative analysis of the three imprinted genes p57(KIP2), IGF2, and H19 总被引:2,自引:0,他引:2
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Hartmann W Waha A Koch A Goodyer CG Albrecht S von Schweinitz D Pietsch T 《The American journal of pathology》2000,157(4):1393-1403
13.
Horike S Mitsuya K Meguro M Kotobuki N Kashiwagi A Notsu T Schulz TC Shirayoshi Y Oshimura M 《Human molecular genetics》2000,9(14):2075-2083
Human chromosome 11p15.5 harbors an intriguing imprinted gene cluster of 1 Mb. This imprinted domain is implicated in a wide variety of malignancies and Beckwith-Wiedemann syndrome (BWS). Recently, several lines of evidence have suggested that the BWS-associated imprinting cluster consists of separate chromosomal domains. We have previously identified LIT1, a paternally expressed antisense RNA within the KvLQT1 locus through a positional screening approach using human monochromosomal hybrids. KvLQT1 encompasses the translocation breakpoint cluster in BWS and patients exhibit frequent loss of maternal methylation at the LIT1 CpG island, implying a regulatory role for the LIT1 locus in coordinate control of the imprinting cluster. Here we generated modified human chromosomes carrying a targeted deletion of the LIT1 CpG island using recombination-proficient chicken DT40 cells. Consistent with the prediction, this mutation abolished LIT1 expression on the paternal chromosome, accompanied by activation of the normally silent paternal alleles of multiple imprinted loci at the centromeric domain including KvLQT1 and p57(KIP2). The deletion had no effect on imprinting of H19 located at the telomeric end of the cluster. Our findings demonstrate that the LIT1 CpG island can act as a negative regulator in cis for coordinate imprinting at the centromeric domain, thereby suggesting a role for the LIT1 locus in a BWS pathway leading to functional inactivation of p57(KIP2). Thus, the targeting and precise modification of human chromosomal alleles using the DT40 cell shuttle system can be used to define regulatory elements that confer long-range control of gene activity within chromosomal domains. 相似文献
14.
The necdin gene is deleted in Prader-Willi syndrome and is imprinted in human and mouse 总被引:9,自引:5,他引:9
Human chromosome 15q11-q13 contains genes that are imprinted and expressed
from only one parental allele. Prader-Willi syndrome (PWS) is due to the
loss of expression of one or more paternally expressed genes on proximal
human chromosome 15q, most often by deletion or maternal uniparental
disomy. Several candidate genes and a putative imprinting centre have been
identified in the deletion region. We report that the human necdin-encoding
gene (NDN) is within the centromeric portion of the PWS deletion region,
between the two imprinted genes ZNF127 and SNRPN. Murine necdin is a
nuclear protein expressed exclusively in differentiated neurons in the
brain. Necdin is postulated to govern the permanent arrest of cell growth
of post-mitotic neurons during murine nervous system development. We have
localized the mouse locus Ndn encoding necdin to chromosome 7 in a region
of conserved synteny with human chromosome 15q11-q13, by genetic mapping in
an interspecific backcross panel. Furthermore, we demonstrate that
expression of Ndn is limited to the paternal allele in RNA from newborn
mouse brain. Expression of NDN is detected in many human tissues, with
highest levels of expression in brain and placenta. NDN is expressed
exclusively from the paternally inherited allele in human fibroblasts. Loss
of necdin gene expression may contribute to the disorder of brain
development in individuals with PWS.
相似文献
15.
Genes subject to genomic imprinting generally occur in clusters of hundreds
of kilobases. These domains exhibit several gamete of origin- dependent
manifestations, including a pattern of asynchronous replication when
studied by fluorescence in situ hybridization (FISH). We find a transition
from asynchronous replication at the imprinted mouse H19 gene to
synchronous replication at the downstream Rpl23 gene, the human homologue
of which appears to be non-imprinted. Two-colour FISH demonstrates that
this transition is due solely to a difference in replication timing between
the upstream and downstream chromatin on the later-replicating (maternal)
chromosome. This difference is lost in mice deleted for the H19 gene body
and 9.9 kb of upstream DNA when this deletion is maternally inherited, with
synchronous replication patterns extending over 110 kb upstream from the
deleted area. No effect is seen when the deletion is paternally inherited.
The presence of a boundary element in this region has been suggested by
observations of position- independent expression of H19 -containing
transgenes and the blocking of accessibility of downstream enhancers to the
upstream Igf2 and Ins2 genes on the maternal chromosome. The FISH studies
presented here demonstrate the insulation of replication patterns within
the imprinted domain from downstream, non-imprinted chromatin, mediated by
an element at the H19 locus which is subject to genomic imprinting.
相似文献
16.
Epigenetic modification and uniparental inheritance of H19 in Beckwith-Wiedemann syndrome. 总被引:5,自引:2,他引:5
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D Catchpoole W W Lam D Valler I K Temple J A Joyce W Reik P N Schofield E R Maher 《Journal of medical genetics》1997,34(5):353-359
Beckwith-Wiedemann syndrome (BWS) is a congenital overgrowth syndrome associated with a characteristic pattern of visceromegaly and predisposition to childhood tumours. BWS is a genetically heterogeneous disorder; most cases are sporadic but approximately 15% are familial and a small number of BWS patients have cytogenetic abnormalities involving chromosome 11p15. Genomic imprinting effects have been implicated in familial and non-familial BWS. We have investigated the molecular pathology of 106 sporadic BWS cases; 17% (14/83) of informative cases had uniparental disomy (UPD) for chromosome 11p15.5. In each case UPD appeared to result from a postzygotic event resulting in mosaicism for segmental paternal isodisomy. The critical region for isodisomy was refined to a 25 cM interval between D11S861 and D11S2071 which contained the IGF2, H19, and p57(KIP2) genes. In three cases isodisomy for 11q markers was detected but this did not extend further than 11q13-q21 suggesting that complete chromosome 11 disomy may not produce a BWS phenotype. The allele specific methylation status of the H19 gene was investigated in 80 sporadic BWS cases. All 13 cases with UPD tested displayed hypermethylation consistent with an excess of paternal H19 alleles. In addition, five of 63 (8%) cases with normal biparental inheritance had H19 hypermethylation consistent with an "imprinting centre" mutation (ICM) or "imprinting error" (IE) lesion. The phenotype of patients with putative ICM/IE mutations was variable and overlapped with that of non-UPD sporadic BWS cases with normal H19 methylation. However, exomphalos was significantly (p < 0.05) more common in the latter group. These findings may indicate differential effects on the expression of imprinted genes in chromosome 11p15 according to the precise molecular pathology. Analysis of H19 methylation is useful for the diagnosis of both UPD or altered imprinting in BWS and shows that a variety of molecular mechanisms may cause relaxation of IGF2 imprinting in BWS. 相似文献
17.
18.
19.
Genomic imprinting, the differential expression of autosomal genes based on their parent of origin, is observed in all eutherian mammals that have been examined. In most instances the genes that are imprinted in one species are imprinted in others as well, suggesting that imprinting predated eutherian radiation. For example, the RNA-coding H19 gene is repressed upon paternal inheritance in all species examined to date. Thus, it is surprising that there is remarkably little sequence conservation among the cis-acting DNA regulatory elements that are required for imprinting of H19 and the tightly linked Igf2 gene. The most conserved characteristic in the imprinting control region (ICR) is the presence of multiple binding sites for the zinc finger protein CTCF, raising the possibility that CTCF binding might be sufficient for the reciprocal imprinting of H19 and Igf2. To investigate whether a human H19 transgene, harboring seven CTCF sites, is correctly recognized and imprinted in the mouse, a 100 kb transgene containing the human H19 gene was introduced into the mouse germline. The human transgene was specifically methylated after passage through the male germline in a copy number-dependent manner, but the methylation was unstable, undergoing progressive loss during development. Consequently, the transgene was highly expressed upon both maternal and paternal inheritance. These results argue that the signals for both the acquisition and maintenance of methylation imprinting are diverging rapidly. 相似文献
20.
Syntenic organization of the mouse distal chromosome 7 imprinting cluster and the Beckwith-Wiedemann syndrome region in chromosome 11p15.5 总被引:8,自引:2,他引:8
Paulsen M; Davies KR; Bowden LM; Villar AJ; Franck O; Fuermann M; Dean WL; Moore TF; Rodrigues N; Davies KE; Hu RJ; Feinberg AP; Maher ER; Reik W; Walter J 《Human molecular genetics》1998,7(7):1149-1159
In human and mouse, most imprinted genes are arranged in chromosomal
clusters. Their linked organization suggests co-ordinated mechanisms
controlling imprinting and gene expression. The identification of local and
regional elements responsible for the epigenetic control of imprinted gene
expression will be important in understanding the molecular basis of
diseases associated with imprinting such as Beckwith- Wiedemann syndrome.
We have established a complete contig of clones along the murine imprinting
cluster on distal chromosome 7 syntenic with the human imprinting region at
11p15.5 associated with Beckwith- Wiedemann syndrome. The cluster comprises
approximately 1 Mb of DNA, contains at least eight imprinted genes and is
demarcated by the two maternally expressed genes Tssc3 (Ipl) and H19 which
are directly flanked by the non-imprinted genes Nap1l4 (Nap2) and Rpl23l
(L23mrp), respectively. We also localized Kcnq1 (Kvlqt1) and Cd81 (Tapa-1)
between Cdkn1c (p57(Kip2)) and Mash2. The mouse Kcnq1 gene is maternally
expressed in most fetal but biallelically transcribed in most neonatal
tissues, suggesting relaxation of imprinting during development. Our
findings indicate conserved control mechanisms between mouse and human, but
also reveal some structural and functional differences. Our study opens the
way for a systematic analysis of the cluster by genetic manipulation in the
mouse which will lead to animal models of Beckwith-Wiedemann syndrome and
childhood tumours.
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