Epigenetic gene silencing in cancer.
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DNA Methylation↗
Biomedical subjects
B Tycko
Publications and source records attributed to B Tycko.
Influence of APOE genotype on familial aggregation of AD in an urban population.
OBJECTIVE: To examine the influence of the proband's APOE genotype on AD among first-degree relatives in a community-based study of African Americans, whites, and Caribbean Hispanics. METHODS: History of AD and demographic information were obtained on 1,073 siblings and parents of 312 patients with AD and 2,722 siblings and parents of 802 nondemented controls. APOE genotyping was performed on all 1,114 patients and controls. RESULTS: A higher proportion of patients with AD (35%) than controls (27%) had one or more APOE-epsilon4 alleles (p = 0.03). When compared with relatives of controls without an APOE-epsilon4 allele, the risk for AD was increased in first-degree relatives of both patients (rate ratio [RR] = 1.9, 95% confidence interval [CI] = 1.2 to 3.1) and controls (RR = 1.8, 95% CI = 1.2 to 2.6) with one or more APOE-epsilone alleles, regardless of ethnic group. There was a similar trend of increased risk in relatives of patients without an APOE-epsilon4 allele, but this was limited to Hispanics and African Americans. CONCLUSIONS: The presence of an APOE-epsilon4 allele increases risk for AD among first-degree relatives, regardless of the probands' disease status, among all ethnic groups. Relatives of patients without an APOE-epsilon4 allele were also at increased risk for AD among Hispanics and African Americans, suggesting that other genes or risk factors may influence risk.
Aged↗
Genomic imprinting and cancer.
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Age Factors↗
A novel pleckstrin homology-related gene family defined by Ipl/Tssc3, TDAG51, and Tih1: tissue-specific expression, chromosomal location, and parental imprinting.
We previously described a gene, Ipl (Tssc3), that is expressed selectively from the maternal allele in placenta, yolk sac, and fetal liver and that maps within the imprinted domain of mouse distal Chromosome (Chr) 7/human Chr 11p15.5 (Hum Mol Genet 6, 2021, 1997). Ipl is similar to TDAG51, a gene that is involved in FAS/CD95 expression. Here we describe another gene, Tih1 (TDAG/Ipl homologue 1), with equivalent sequence similarity to Ipl. Structural prediction indicates that the products of these three genes share a central motif resembling a pleckstrin-homology (PH) domain, and TIH1 protein has weak sequence similarity to the PH-domain protein SEC7/CYTOHESIN. Like Ipl, Tih1 is a small gene with a single small intron. Tih1 maps to distal mouse Chr 1 and human Chr 1q31, chromosomal regions that have not shown evidence for imprinting and, in contrast to Ipl, Tih1 is expressed equally from both parental alleles. Ipl, Tih1, and TDAG51 have overlapping but distinct patterns of expression. Tih1 and TDAG51 are expressed in multiple fetal and adult tissues. In contrast, during early mouse development Ipl mRNA and protein are highly specific for two tissues involved in maternal/fetal exchange: visceral endoderm of the yolk sac and labyrinthine trophoblast of the placenta. These findings highlight the dominance of chromosomal context over gene structure in some examples of parental imprinting and extend previous evidence for placenta-specific expression of imprinted genes. The data also define a new subfamily of PH domain genes.
Amino Acid Motifs↗
Multipoint analysis of human chromosome 11p15/mouse distal chromosome 7: inclusion of H19/IGF2 in the minimal WT2 region, gene specificity of H19 silencing in Wilms' tumorigenesis and methylation hyper-dependence of H19 imprinting.
WT2 is defined by maternal-specific loss of heterozygosity (LOH) on chromosome 11p15.5 in Wilms' tumors (WTs). The imprinted H19 gene, in this region, is silenced and hypermethylated in most WTs, and this is linked to pathological biallelic expression of IGF2. However, H19 and IGF2 lie within a larger imprinted domain, and the gene specificity of H19 epimutation has been a persistent question. To address this, we assessed LOH, gene expression and DNA methylation at multiple sites in and around the imprinted domain. LOH mapping showed that the entire domain, including IGF2/H19, is within the minimal WT2 region. Genes within the domain, including IPL/TSSC3/BWR1C, IMPT1/ORCTL2/BWR1A/TSSC5, KvLQT1/KCNA9 and TAPA1/CD81, as well as the zinc finger gene ZNF195/ZNFP104 near the centromeric border, were expressed persistently in many WTs. DNA hypermethylation was not detected with 5" upstream probes for IPL, IMPT1, KvLQT1 and ZNF195 in WTs or WT-associated kidneys. Fully developed WTs showed variable hypomethylation at an imprinted CpG island in a KvLQT1 intron, but this was only complete in the cases with LOH and was not observed in pre-neoplastic WT-associated kidneys with H19 epimutation. Analysis of the corresponding region of mouse chromosome 7 using methyltransferase-hypomorphic mice showed that the H19 imprint was fully erased, but that the allelic bias at Ipl, Impt1, p57 Kip2 and, to a lesser extent, Kvlqt1, persisted. Pre-existing massive allelic asymmetry for DNA methylation and hyper-dependence of transcription on methylation status may underlie the mechanism of gene-specific silencing of H19 in Wilms' tumorigenesis.
Animals↗
A common Hpa I RFLP of apolipoprotein C-I increases gene transcription and exhibits an ethnically distinct pattern of linkage disequilibrium with the alleles of apolipoprotein E.
Apolipoprotein (apo) C-I is a constituent of triglyceride-rich lipoproteins (TGRL) that interferes with their hepatic clearance. Functional polymorphism in the apoC-I gene has not been established. We determined that an Hpa I site variably present at -317 relative to the apoC-I gene is produced by a 4-bp CGTT insertion. The apoC-I Hpa I alleles showed an ethnically distinct pattern of linkage disequilibrium with the alleles of the adjacent apoE gene. The frequency of apoC-I Hpa I-positive (H2) with apoE varepsilon2 was 0. 98, without significant ethnic difference. In contrast, the frequency of H2 with apoE epsilon4 was 0.85 in European-Americans but only 0.55 in African-Americans (P < 0.001). The frequency of H2 with apoE epsilon3 was 0.02 in European-Americans and 0.08 in African-Americans (P < 0.001). African-American apoE epsilon3/epsilon3 carriers of apoC-I H2 had 19% lower fasting triglyceride levels than H1 homozygotes (P = 0.03) along with 18% higher HDL-cholesterol levels (P = 0.02). ApoB levels were 21% lower (P = 0.002). H2-allelic reporter-gene constructions showed 50% higher expression in transient transfection studies. We localized the source of this difference in expression to the CGTT insertion itself. Deletion studies of the H1 allele showed a negative transcriptional effect of the polymorphic region. An H1 oligodeoxynucleotide showed specific binding of a hepatoma-cell nuclear protein not evident with an H2 oligodeoxynucleotide. The H2 sequence may decrease the binding of a negatively acting transcription factor, leading to overexpression of apoC-I. This may produce a functional effect on lipoprotein levels but confirmation is needed in other populations.
Alleles↗
The APOE-epsilon4 allele and the risk of Alzheimer disease among African Americans, whites, and Hispanics.
CONTEXT: Although the association between Alzheimer disease (AD) and the apolipoprotein E epsilon4 (APOE-epsilon4) allele has been confirmed worldwide, it appears to be inconsistent among African Americans, Hispanics, and Nigerians. OBJECTIVE: To investigate the association between the APOE-epsilon4 allele and AD in elderly African Americans, Hispanics, and whites. DESIGN: Prospective, population-based, longitudinal study over a 5-year period (1991-1996). SETTING: The Washington Heights-Inwood community of New York City. PARTICIPANTS: A total of 1079 Medicare recipients without AD or a related disorder at baseline. MAIN OUTCOME MEASURES: Risk of clinically diagnosed AD in the 3 ethnic groups and among individuals with and without an APOE-epsilon4 allele. RESULTS: Compared with individuals with the APOE-epsilon3/epsilon3 genotype, the relative risk (RR) of AD associated with 1 or more copies of the APOE-epsilon4 allele was significantly increased among whites (RR, 2.5; 95% confidence interval [CI], 1.1-6.4), but not among African Americans (RR, 1.0; 95% CI, 0.6-1.6) or Hispanics (RR, 1.1; 95% CI, 0.7-1.6). In the absence of the APOE-epsilon4 allele, the cumulative risks of AD to age 90 years, adjusted for education and sex, were 4 times higher for African Americans (RR, 4.4; 95% CI, 2.3-8.6) and 2 times higher for Hispanics (RR, 2.3; 95% CI, 1.2-4.3) than for whites. In the presence of an APOE-epsilon4 allele, the cumulative risk of AD to age 90 years was similar for individuals in all 3 ethnic groups. CONCLUSION: The presence of an APOE-epsilon4 allele is a determinant of AD risk in whites, but African Americans and Hispanics have an increased frequency of AD regardless of their APOE genotype. These results suggest that other genes or risk factors may contribute to the increased risk of AD in African Americans and Hispanics.
Aged↗
Monoallelic expression: 'there can only be one'.
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Alleles↗
IMPT1, an imprinted gene similar to polyspecific transporter and multi-drug resistance genes.
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.
Adult↗
Earlier onset of Alzheimer's disease in men with Down syndrome.
BACKGROUND: Virtually all individuals with Down syndrome (DS) have neuropathologic changes characteristic of Alzheimer's disease (AD) beginning at 40 years of age. Few studies have examined factors that influence age at onset of AD in DS. We investigated whether sex differences in age at onset and risk of AD among adults with DS are similar to those observed in the general population and whether the effect of sex on risk of AD is modified by apolipoprotein E (APOE) genotype. METHODS: A community-based sample of 111 adults with cytogenetically confirmed DS (34 to 71 years of age) was ascertained through the New York State Developmental Disabilities system. A semistructured interview with caregivers and review of medical records was used to ascertain the presence or absence of AD. APOE genotyping was carried out without knowledge of the subject's medical history or clinical diagnosis. RESULTS AND CONCLUSIONS: Both male gender and the presence of an APOE epsilon4 allele were associated with an earlier onset of AD. Compared with women, men with DS were three times as likely to develop AD. Compared with those with the APOE 3/3 genotype, adults with DS with the 3/4 or 4/4 genotypes were four times as likely to develop AD. No individual with an APOE epsilon2 allele developed AD. No evidence of interaction of sex and APOE genotype was found in risk of AD. The higher risk of AD in men may be related to differences in hormonal function between men and women with DS that are distinct from those in the general population.
Adult↗
PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer.
Mapping of homozygous deletions on human chromosome 10q23 has led to the isolation of a candidate tumor suppressor gene, PTEN, that appears to be mutated at considerable frequency in human cancers. In preliminary screens, mutations of PTEN were detected in 31% (13/42) of glioblastoma cell lines and xenografts, 100% (4/4) of prostate cancer cell lines, 6% (4/65) of breast cancer cell lines and xenografts, and 17% (3/18) of primary glioblastomas. The predicted PTEN product has a protein tyrosine phosphatase domain and extensive homology to tensin, a protein that interacts with actin filaments at focal adhesions. These homologies suggest that PTEN may suppress tumor cell growth by antagonizing protein tyrosine kinases and may regulate tumor cell invasion and metastasis through interactions at focal adhesions.
Amino Acid Sequence↗
Apolipoprotein E epsilon4 and the risk of dementia with stroke. A population-based investigation.
OBJECTIVE: To investigate the association between the apolipoprotein E (APOE) genotypes and dementia in patients with stroke, defined as either vascular dementia (VaD) or Alzheimer disease with cerebrovascular disease (AD with CVD). DESIGN AND SETTING: Population-based, case-control study from Rotterdam, the Netherlands, and New York City. PARTICIPANTS: A total of 187 patients with dementia and stroke were compared with 507 controls similar in age and ethnic group. MAIN OUTCOME MEASURES: The APOE allele frequencies in patients and controls; the odds ratio of dementia with stroke, VaD, and AD with CVD, adjusted for age, sex, residency, and education; and the percent attributable risk related to the APOE epsilon4 allele. RESULTS: Overall, patients with dementia and stroke had a higher APOE epsilon4 allele frequency than controls. Compared with APOE epsilon3 homozygote individuals, APOE epsilon4 homozygotes had a 7-fold increased risk of dementia with stroke (OR=6.9; 95% CI, 1.6-29.4), while APOE epsilon4 heterozygotes had nearly a 2-fold increase in risk (OR=1.8; 95% CI, 1.2-2.7). Risks associated with APOE epsilon4 were elevated regardless of the subtype of dementia with stroke or age or sex. The percent attributable risk related to the APOE epsilon4 allele among demented patients with stroke was 41% overall, 33% among those with VaD, and 44% among those with AD with CVD. CONCLUSION: The APOE epsilon4 allele is a genetic risk factor for dementia with stroke, including VaD and AD with CVD. This may imply shared genetic susceptibility to dementia associated with stroke and AD. Alternatively, the category of patients with dementia and stroke, including VaD as currently defined, may include patients with AD.
Aged↗
Apolipoprotein E epsilon4 and incidence of Alzheimer disease in a community population of older persons.
OBJECTIVE: To examine the relation between apolipoprotein E status and risk of Alzheimer disease (AD) in a defined population and estimate the fraction of incident AD attributable to the epsilon4 allele. DESIGN: Community-based cohort study. SETTING: East Boston, Mass. PARTICIPANTS: A random sample of 578 community residents aged 65 years and older free of AD. MAIN OUTCOME MEASURE: Clinical diagnosis of AD by uniform, structured evaluation. RESULTS: The increased risk of AD associated with the presence of the epsilon4 allele was less than that found in most family and case-control studies. Persons with the epsilon4/epsilon4 or epsilon3/epsilon4 genotypes had 2.27 (95% confidence interval, 1.06-4.89) times the risk of incident disease compared with those with the epsilon3/epsilon3 genotype. The epsilon4 allele accounted for a fairly small fraction of the incidence of AD; if the allele did not exist or had no effect on disease risk, the incidence would be reduced by only 13.7%. The effect of the epsilon4 allele on risk of AD did not appear to vary with age. CONCLUSIONS: The apolipoprotein E epsilon4 allele is an important genetic risk factor for AD but accounts for a fairly small fraction of disease occurrence in this population-based study. Continued efforts to identify other environmental and genetic risk factors are warranted.
Aged↗
The absence of an apolipoprotein epsilon4 allele is associated with a more aggressive form of Alzheimer's disease.
We investigated the relationship between APOE genotype and rate of disease progression and survival in 99 patients with probable Alzheimer's disease (AD) who were followed biannually for up to 6 years. Patients were stratified into two groups, those with and without at least one APOE epsilon4 allele. The rate of decline in modified Mini-Mental State Examination scores was slower, the presence of extrapyramidal signs was decreased, and the development of myoclonus occurred later among patients with APOE epsilon4 alleles compared with patients with other genotypes. Compared with patients without an APOE epsilon4 allele, the risk of mortality was also decreased in patients with at least one epsilon4 allele (RR = 0.38; CI = 0.17-0.84, p < 0.02). Because the decline in mental ability as well as the development of myoclonus and extrapyramidal signs are consistent manifestations of disease progression, our results imply that APOE epsilon4 is associated with a less aggressive form of AD.
Age of Onset↗
DNA methylation in genomic imprinting.
As a reversible epigenetic modification which can affect gene expression, DNA methylation has been an attractive candidate for the biochemical mechanism of genomic imprinting. Many correlations in mice and humans link allele-specific DNA methylation to the allele-restricted RNA expression which is the hallmark of imprinted genes. Moreover, abnormal DNA methylation accompanies the pathological functional imprinting of certain human genes on chromosome 11p15.5 in Wilms' tumors and in the Beckwith-Weidemann syndrome and on chromosome 15q11-13 in the Prader-Willi and Angelman syndromes. A role for DNA methylation in maintaining the transcriptional silence of imprinted alleles at some loci has been supported by pharmacological manipulation with 5-aza-2'-deoxycytidine and by experiments with methyltransferase deletion mice. Gametic differences in DNA methylation could also account for the initiation of imprints, but this remains unproven. Comprehensive physical models for the role of DNA methylation in imprinting must account not only for local allele-restricted gene expression but also for the existence of large chromosomal domains containing multiple coordinately imprinted genes.
Angelman Syndrome↗
Coding mutations in p57KIP2 are present in some cases of Beckwith-Wiedemann syndrome but are rare or absent in Wilms tumors.
The Beckwith-Wiedemann syndrome (BWS) is marked by fetal organ overgrowth and conveys a predisposition to certain childhood tumors, including Wilms tumor (WT). The genetics of BWS have implicated a gene that maps to chromosome 11p15 and is paternally imprinted, and the gene encoding the cyclin-cdk inhibitor p57KIP2 has been a strong candidate. By complete sequencing of the coding exons and intron/exon junctions, we found a maternally transmitted coding mutation in the cdk-inhibitor domain of the KIP2 gene in one of five cases of BWS. The BWS mutation was an in-frame three-amino-acid deletion that significantly reduced but did not fully abrogate growth-suppressive activity in a transfection assay. In contrast, no somatic coding mutations in KIP2 were found in a set of 12 primary WTs enriched for cases that expressed KIP2 mRNA, including cases with and without 11p15.5 loss of heterozygosity. Two other 11p15.5 loci, the linked and oppositely imprinted H19 and IGF2 genes, have been previously implicated in WT pathogenesis, and several of the tumors with persistent KIP2 mRNA expression and absence of KIP2 coding mutations showed full inactivation of H19. These data suggest that KIP2 is a BWS gene but that it is not uniquely equivalent to the 11p15.5 "WT2" tumor-suppressor locus.
Beckwith-Wiedemann Syndrome↗
The IPL gene on chromosome 11p15.5 is imprinted in humans and mice and is similar to TDAG51, implicated in Fas expression and apoptosis.
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.
Amino Acid Sequence↗
Role of the H19 gene in Syrian hamster embryo cell tumorigenicity.
Carcinogen-induced transformation in Syrian hamster embryo (SHE) cells is a multistage process characterized by specific genetic alterations at each stage in the transformation process. Loss of H19 gene expression is one of the earliest events observed, occurring in approximately 75% of the morphologically transformed cells and the subsequently derived tumorigenic cells. To investigate the effect the loss of H19 expression has on SHE cell tumorigenicity, H19 expression was reestablished in a tumorigenic SHE cell lineage that lacked H19 expression. H19 reexpression had little effect on cellular growth in vitro but did retard tumor growth in nude mice. Analysis of the tumors that did develop from cells containing the H19 gene indicated that loss of exogenous H19 gene expression was probably due to changes in DNA methylation. These results demonstrate that alterations in H19 gene expression play an important role in SHE cell tumorigenicity.
Animals↗