共查询到20条相似文献,搜索用时 61 毫秒
1.
2.
3.
The ICF syndrome, a DNA methyltransferase 3B deficiency and immunodeficiency disease 总被引:9,自引:0,他引:9
Ehrlich M 《Clinical immunology (Orlando, Fla.)》2003,109(1):17-28
Only one human disease that involves Mendelian inheritance of immunodeficiency and aberrant DNA methylation has been identified. This is a rare chromosome breakage disease called the immunodeficiency, centromeric region instability, and facial anomalies syndrome (ICF). Its diagnostic characteristics are agammaglobulinemia with B cells as well as DNA rearrangements targeted to the centromere-adjacent heterochromatic region (qh) of chromosomes 1, 16, and sometimes 9 in mitogen-stimulated lymphocytes. These rearrangement-prone regions show DNA hypomethylation in all examined ICF cell populations. This review summarizes our knowledge about the immunological symptoms of ICF; the nature of DNMT3B mutations in ICF patients; the phenotypes of DNA hypomethylation mutants in humans, mice, and Arabidopsis; the epigenetics of ICF; and ICF-specific RNA expression and cell-surface antigen expression in lymphoblastoid cell lines. Comparisons of ICF and control lymphoblastoid cell lines and ICF patients' symptoms suggest an involvement of DNA methylation in the late stages of lymphocyte maturation. 相似文献
4.
Escape from gene silencing in ICF syndrome: evidence for advanced replication time as a major determinant 总被引:5,自引:0,他引:5
Hansen RS Stöger R Wijmenga C Stanek AM Canfield TK Luo P Matarazzo MR D'Esposito M Feil R Gimelli G Weemaes CM Laird CD Gartler SM 《Human molecular genetics》2000,9(18):2575-2587
Chromosomal abnormalities associated with hypomethylation of classical satellite regions are characteristic for the ICF immunodeficiency syndrome. We, as well as others, have found that these effects derive from mutations in the DNMT3B DNA methyltransferase gene. Here we examine further the molecular phenotype of ICF cells and report several examples of extensive hypomethylation that are associated with advanced replication time, nuclease hypersensitivity and a variable escape from silencing for genes on the inactive X and Y chromosomes. Our analysis suggests that all genes on the inactive X chromosome may be extremely hypomethylated at their 5' CpG islands. Our studies of G6PD in one ICF female and SYBL1 in another ICF female provide the first examples of abnormal escape from X chromosome inactivation in untransformed human fibroblasts. XIST RNA localization is normal in these cells, arguing against an independent silencing role for this RNA in somatic cells. SYBL1 silencing is also disrupted on the Y chromosome in ICF male cells. Increased chromatin sensitivity to nuclease was found at all hypomethylated promoters examined, including those of silenced genes. The persistence of inactivation in these latter cases appears to depend critically on delayed replication of DNA because escape from silencing was only seen when replication was advanced to an active X-like pattern. 相似文献
5.
6.
Dupont C Guimiot F Perrin L Marey I Smiljkovski D Le Tessier D Lebugle C Baumann C Bourdoncle P Tabet AC Aboura A Benzacken B Dupont JM 《Clinical genetics》2012,82(2):187-192
ICF (immunodeficiency, centromeric region instability, facial anomalies) syndrome is a rare autosomal recessive disorder characterised by severe immunodeficiency, craniofacial anomalies and chromosome instability. Chromosome analyses from blood samples show a high frequency of decondensation of pericentromeric heterochromatin (PH) and rearrangements involving chromosomes 1 and 16. It is the first and, as far as we know, the only disease associated with a mutation in a DNA methyltransferase gene, DNMT3B, with significant hypomethylation of the classical satellite DNA, the major component of the juxtacentromeric heterochromatin. To better understand the complex links between the hypomethylation of the satellite DNA, the cytogenetic anomalies and the clinical features of ICF syndrome, we performed three-dimensional (3D) FISH on preserved cells from a patient with a suspected ICF phenotype. Analysis of DNMT3B did not reveal any mutation in our patient, making this case an ICF type 2. The results of 3D-FISH showed a statistically significant change in the intranuclear position of PH of chromosome 1 in cells of the patient as compared to normal cells. It is difficult to understand how a defect in the methylation pathway can be responsible for the various symptoms of this condition. From our observations we suggest a mechanistic link between the reorganisation of the nuclear architecture and the altered gene expression. 相似文献
7.
8.
DNA methyltransferase 3B mutations linked to the ICF syndrome cause dysregulation of lymphogenesis genes. 总被引:7,自引:0,他引:7
M Ehrlich K L Buchanan F Tsien G Jiang B Sun W Uicker C M Weemaes D Smeets K Sperling B H Belohradsky N Tommerup D E Misek J M Rouillard R Kuick S M Hanash 《Human molecular genetics》2001,10(25):2917-2931
9.
Defective de novo methylation of viral and cellular DNA sequences in ICF syndrome cells 总被引:1,自引:0,他引:1
Tao Q Huang H Geiman TM Lim CY Fu L Qiu GH Robertson KD 《Human molecular genetics》2002,11(18):2091-2102
ICF syndrome (immunodeficiency, centromere instability and facial anomalies) is a recessive human genetic disorder resulting from mutations in the DNA methyltransferase 3B (DNMT3B) gene. Patients with this disease exhibit numerous chromosomal abnormalities, including anomalous decondensation, pairing, separation and breakage, primarily involving the pericentromeric regions of chromosomes 1 and 16. Global levels of DNA methylation in ICF cells are only slightly reduced; however, certain repetitive sequences and genes on the inactive X chromosome of female ICF patients are significantly hypomethylated. In the present report, we analyze the molecular defect of de novo methylation in ICF cells in greater detail by making use of a model Epstein-Barr virus (EBV)-based system and three members of the unique cellular cancer-testis (C-T) gene family. Results with the EBV-based system indicate that de novo methylation of newly introduced viral sequences is defective in ICF syndrome. Limited de novo methylation capacity is retained in ICF cells, indicating that the mutations in DNMT3B are not complete loss-of-function mutations or that other DNMTs cooperate with DNMT3B. Analysis of three C-T genes (two on the X chromosome and one autosomal) revealed that loss of methylation from cellular gene sequences is heterogeneous, with both autosomal and X chromosome-based genes demonstrating sensitivity to mutations in DNMT3B. Aberrant hypomethylation at a number of loci examined correlated with altered gene expression levels. Lastly, no consistent changes in the protein levels of the DNA methyltransferases were noted when normal and ICF cell lines were compared. 相似文献
10.
Masaki Takasugi Koji Hayakawa Daisuke Arai Kunio Shiota 《Mechanisms of ageing and development》2013,134(7-8):331-337
In mammals, differences in liver function and aging have been observed between sexes; however, the epigenetic mechanisms underlying such differences remain largely unexplored. In this study, we investigated sex- and age-dependent DNA methylation status in the mouse liver. We analyzed 90 known sex-differentially expressed genes, and identified sex-dependent methylation in Zfp809, Hsd3b5, Treh, Cxcl11, Cyp17a1, and Nnmt genes. After 4 weeks of age, we noted the gradual establishment of sex-dependent hypomethylation in each of these genes in either males or females. The exposure of male mice to female-like growth hormone (GH) profile repressed male-predominant hypomethylation and promoted female-predominant hypomethylation. The occurrence of age-dependent hypomethylation, including at loci for which we also observed sex-dependent changes in DNA methylation, was accompanied by the downregulation of DNMT3A/B. In addition, we found that age-dependent hypomethylation was promoted through liver regeneration induced by partial hepatectomy, suggesting that DNMT activities were not enough to retain methylation levels. In conclusion, our results demonstrate that sex-dependent GH profiles influence the age-progressive hypomethylation under decreased DNMT3A/B levels in certain regions of the genome. 相似文献
11.
Dysregulation of DNA methylation induced by past arsenic treatment causes persistent genomic instability in mammalian cells
下载免费PDF全文
![点击此处可从《Environmental and molecular mutagenesis》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Catherine B. Klein 《Environmental and molecular mutagenesis》2016,57(2):137-150
The mechanisms by which arsenic‐induced genomic instability is initiated and maintained are poorly understood. To investigate potential epigenetic mechanisms, in this study we evaluated global DNA methylation levels in V79 cells and human HaCaT keratinocytes at several time points during expanded growth of cell cultures following removal of arsenite exposures. We have found altered genomic methylation patterns that persisted up to 40 cell generations in HaCaT cells after the treatments were withdrawn. Moreover, mRNA expression levels were evaluated by RT‐PCR for DNMT1, DNMT3A, DNMT3B, HMLH1, and HMSH2 genes, demonstrating that the down regulation of DNMT3A and DNMT3B genes, but not DNMT1, occurred in an arsenic dose‐dependent manner, and persisted for many cell generations following removal of the arsenite, offering a plausible mechanism of persistently genotoxic arsenic action. Analyses of promoter methylation status of the DNA mismatch repair genes HMLH1 and HMSH2 show that HMSH2, but not HMLH1, was epigenetically regulated by promoter hypermethylation changes following arsenic treatment. The results reported here demonstrate that arsenic exposure promptly induces genome‐wide global DNA hypomethylation, and some specific gene promoter methylation changes, that persist for many cell generations following withdrawal of arsenite, supporting the hypothesis that the cells undergo epigenetic reprogramming at both the gene and genome level that is durable over many cell generations in the absence of further arsenic treatment. These DNA methylation changes, in concert with other known epigenome alterations, are likely contributing to long‐lasting arsenic‐induced genomic instability that manifests in several ways, including aberrant chromosomal effects. Environ. Mol. Mutagen. 57:137–150, 2016. © 2015 Wiley Periodicals, Inc. 相似文献
12.
Jiang YL Rigolet M Bourc'his D Nigon F Bokesoy I Fryns JP Hultén M Jonveaux P Maraschio P Mégarbané A Moncla A Viegas-Péquignot E 《Human mutation》2005,25(1):56-63
ICF syndrome is a rare autosomal recessive disease characterized by variable immunodeficiency, centromeric instability, and facial abnormalities. Mutations in the catalytic domain of DNMT3B, a gene encoding a de novo DNA methyltransferase, have been recognized in a subset of patients. ICF syndrome is a genetic disease directly related to a genomic methylation defect that mainly affects classical satellites 2 and 3, both components of constitutive heterochromatin. The variable incidence of DNMT3B mutations and the differential methylation defect of alpha satellites allow the identification of two types of patients, both showing an undermethylation of classical satellite DNA. This classification illustrates the specificity of the methylation process and raises questions about the genetic heterogeneity of the ICF syndrome. 相似文献
13.
Lana E Mégarbané A Tourrière H Sarda P Lefranc G Claustres M De Sario A 《European journal of human genetics : EJHG》2012,20(10):1044-1050
ICF syndrome is a rare autosomal recessive disorder that is characterized by Immunodeficiency, Centromeric instability, and Facial anomalies. In all, 60% of ICF patients have mutations in the DNMT3B (DNA methyltransferase 3B) gene, encoding a de novo DNA methyltransferase. In ICF cells, constitutive heterochromatin is hypomethylated and decondensed, metaphase chromosomes undergo rearrangements (mainly involving juxtacentromeric regions), and more than 700 genes are aberrantly expressed. This work shows that DNA replication is also altered in ICF cells: (i) heterochromatic genes replicate earlier in the S-phase; (ii) global replication fork speed is higher; and (iii) S-phase is shorter. These replication defects may result from chromatin changes that modify DNA accessibility to the replication machinery and/or from changes in the expression level of genes involved in DNA replication. This work highlights the interest of using ICF cells as a model to investigate how DNA methylation regulates DNA replication in humans. 相似文献
14.
ICF syndrome in a girl with DNA hypomethylation but without detectable DNMT3B mutation 总被引:1,自引:0,他引:1
Kubota T Furuumi H Kamoda T Iwasaki N Tobita N Fujiwara N Goto Y Matsui A Sasaki H Kajii T 《American journal of medical genetics. Part A》2004,(3):290-293
A 3-year-old girl with phenotypic and cytogenetic manifestations of the ICF syndrome and DNA hypomethylation but without DNMT3B gene mutation is described. At age 3 months, she had an apneic spell that left her with spastic paraplegia and severe mental retardation. At age 8 months, she suffered meningococcal meningitis and sepsis. When seen by us at age 3 years with virilization, she had a cleft plate, macroglossia, and an atrial septal defect. An adenoma was surgically removed from the right adrenal cortex. Her serum immunoglobulin levels were normal except IgA at the low normal border. Her lymphocytes showed paracentromeric stretching of chromosomes 1 and 16 in 7% of metaphases, and multiradial figures involving these chromosomes in 1% of cells. Hypomethylation of classical satellite 2 DNA was observed with BstBI digestion, but in a lesser degree than those in the individuals with proven DNMT3B mutations. No mutation was found in the coding and promoter regions of the gene. Several alternative interpretations were considered to explain the low frequencies of chromosomal instabilities and the lower degree of DNA hypomethylation, and undetected DNA3B mutations. A mutation may be present in the gene but undetected, present in other DNA methyltransferases (DNMT) genes or in a DNMT-associated protein gene. 相似文献
15.
16.
A novel deletion in ZBTB24 in a Lebanese family with immunodeficiency, centromeric instability, and facial anomalies syndrome type 2 总被引:1,自引:0,他引:1
Chouery E Abou-Ghoch J Corbani S El Ali N Korban R Salem N Castro C Klayme S Azoury-Abou Rjeily M Khoury-Matar R Debo G Germanos-Haddad M Delague V Lefranc G Mégarbané A 《Clinical genetics》2012,82(5):489-493
17.
E.S.S. de Araújo L.R. Vasques R. Stabellini A.C.V. Krepischi L.V. Pereira 《Brazilian journal of medical and biological research》2014,47(12):1029-1035
DNA methylation is essential in X chromosome inactivation and genomic imprinting,
maintaining repression of XIST in the active X chromosome and
monoallelic repression of imprinted genes. Disruption of the DNA methyltransferase
genes DNMT1 and DNMT3B in the HCT116 cell line (DKO
cells) leads to global DNA hypomethylation and biallelic expression of the imprinted
gene IGF2 but does not lead to reactivation of XIST
expression, suggesting that XIST repression is due to a more stable
epigenetic mark than imprinting. To test this hypothesis, we induced acute
hypomethylation in HCT116 cells by 5-aza-2′-deoxycytidine (5-aza-CdR) treatment
(HCT116-5-aza-CdR) and compared that to DKO cells, evaluating DNA methylation by
microarray and monitoring the expression of XIST and imprinted genes
IGF2, H19, and PEG10. Whereas
imprinted genes showed biallelic expression in HCT116-5-aza-CdR and DKO cells, the
XIST locus was hypomethylated and weakly expressed only under
acute hypomethylation conditions, indicating the importance of XIST
repression in the active X to cell survival. Given that DNMT3A is the only active
DNMT in DKO cells, it may be responsible for ensuring the repression of
XIST in those cells. Taken together, our data suggest that
XIST repression is more tightly controlled than genomic
imprinting and, at least in part, is due to DNMT3A. 相似文献
18.
19.
Do mutations in DNMT3A/3B affect global DNA hypomethylation among benzene‐exposed workers in Southeast China?: Effects of mutations in DNMT3A/3B on global DNA hypomethylation
下载免费PDF全文
![点击此处可从《Environmental and molecular mutagenesis》网站下载免费的PDF全文](/ch/ext_images/free.gif)
《Environmental and molecular mutagenesis》2017,58(9):678-687
Global DNA hypomethylation is commonly observed in benzene‐exposed workers, but the underlying mechanisms remain unclear. We sought to discover the relationships among reduced white blood cell (WBC) counts, micronuclear (MN) frequency, and global DNA methylation to determine whether there were associations with mutations in DNMT3A/3B. Therefore, we recruited 410 shoe factory workers and 102 controls from Wenzhou in Zhenjiang Province. A Methylated DNA Quantification Kit was used to quantify global DNA methylation, and single nucleotide polymorphisms (SNPs) in DNMT3A (rs36012910, rs1550117, and R882) and DNMT3B (rs1569686, rs2424909, and rs2424913) were identified using the restriction fragment length polymorphism method. A multilinear regression analysis demonstrated that the benzene‐exposed workers experienced significant global DNA hypomethylation compared with the controls (β = −0.51, 95% CI: −0.69 to −0.32, P < 0.001). The DNMT3A R882 mutant allele (R882H and R882C) (β = −0.25, 95% CI: −0.54 to 0.04, P = 0.094) and the DNMT3B rs2424909 GG allele (β = −0.37, 95% CI: −0.70 to −0.03, P = 0.031) were significantly associated with global DNA hypomethylation compared with the wild‐type genotype after adjusting for confounding factors. Furthermore, the MN frequency in the R882 mutant allele (R882H and R882C) (FR = 1.18, 95% CI: 0.99 to 1.40, P = 0.054) was higher than that of the wild‐type. The results imply that hypomethylation occurs due to benzene exposure and that mutations in DNMTs are significantly associated with global DNA methylation, which might have influenced the induction of MN following exposure to benzene. Environ. Mol. Mutagen. 58:678–687, 2017. © 2017 Wiley Periodicals, Inc. 相似文献
20.
Corry MR Weemaes Maarten JD van Tol Jun Wang Monique M van Ostaijen-ten Dam Marja CJA van Eggermond Peter E Thijssen Caner Aytekin Nicola Brunetti-Pierri Mirjam van der Burg E Graham Davies Alina Ferster Dieter Furthner Giorgio Gimelli Andy Gennery Barbara Kloeckener-Gruissem Stephan Meyn Cynthia Powell Ismail Reisli Catharina Schuetz Ansgar Schulz Andrea Shugar Peter J van den Elsen Silvère M van der Maarel 《European journal of human genetics : EJHG》2013,21(11):1219-1225
Immunodeficiency with centromeric instability and facial anomalies (ICF) syndrome is a primary immunodeficiency, predominantly characterized by agammaglobulinemia or hypoimmunoglobulinemia, centromere instability and facial anomalies. Mutations in two genes have been discovered to cause ICF syndrome: DNMT3B and ZBTB24. To characterize the clinical features of this syndrome, as well as genotype–phenotype correlations, we compared clinical and genetic data of 44 ICF patients. Of them, 23 had mutations in DNMT3B (ICF1), 13 patients had mutations in ZBTB24 (ICF2), whereas for 8 patients, the gene defect has not yet been identified (ICFX). While at first sight these patients share the same immunological, morphological and epigenetic hallmarks of the disease, systematic evaluation of all reported informative cases shows that: (1) the humoral immunodeficiency is generally more pronounced in ICF1 patients, (2) B- and T-cell compartments are both involved in ICF1 and ICF2, (3) ICF2 patients have a significantly higher incidence of intellectual disability and (4) congenital malformations can be observed in some ICF1 and ICF2 cases. It is expected that these observations on prevalence and clinical presentation will facilitate mutation-screening strategies and help in diagnostic counseling. 相似文献