Human Molecular Genetics, 2002, Vol. 11, No. 18 2091-2102
© 2002 Oxford University Press
Defective de novo methylation of viral and cellular DNA sequences in ICF syndrome cells
1Tumor Virology Laboratory, Johns Hopkins Singapore, Level 5 Clinical Research Center (MD11), NUS, 10 Medical Drive, Singapore 117597 and 2Epigenetic Gene Regulation and Cancer Section, NCI, NIH, Building 41, Room C306, 41 Library Drive, Bethesda, MD 20892, USA
Received April 10, 2002; Accepted June 24, 2002
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.
* To whom correspondence should be addressed. Tel: +1 3015948055; Fax: +1 3014964951; Email: robertk{at}mail.nih.gov
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  Y. Wang, J. Li, Y. Cui, T. Li, K. M. Ng, H. Geng, H. Li, X.-s. Shu, H. Li, W. Liu, et al. CMTM3, Located at the Critical Tumor Suppressor Locus 16q22.1, Is Silenced by CpG Methylation in Carcinomas and Inhibits Tumor Cell Growth through Inducing Apoptosis Cancer Res., June 15, 2009; 69(12): 5194 - 5201. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Cui, L.-Y. Xu, Z.-Y. Shen, Q. Tao, S.-Y. Gao, Z. Lv, Z.-P. Du, W.-K. Fang, and E.-M. Li NGALR Is Overexpressed and Regulated by Hypomethylation in Esophageal Squamous Cell Carcinoma Clin. Cancer Res., December 1, 2008; 14(23): 7674 - 7681. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Jin, Q. Tao, J. Peng, H. M. Soo, W. Wu, J. Ying, C. R. Fields, A. L. Delmas, X. Liu, J. Qiu, et al. DNA methyltransferase 3B (DNMT3B) mutations in ICF syndrome lead to altered epigenetic modifications and aberrant expression of genes regulating development, neurogenesis and immune function Hum. Mol. Genet., March 1, 2008; 17(5): 690 - 709. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Ying, H. Li, J. Yu, K. M. Ng, F. F. Poon, S. C. C. Wong, A. T.C. Chan, J. J.Y. Sung, and Q. Tao WNT5A Exhibits Tumor-Suppressive Activity through Antagonizing the Wnt/ -Catenin Signaling, and Is Frequently Methylated in Colorectal Cancer Clin. Cancer Res., January 1, 2008; 14(1): 55 - 61. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Fu, Y.-R. Qin, D. Xie, L. Hu, D. L. Kwong, G. Srivastava, S. W. Tsao, and X.-Y. Guan Characterization of a Novel Tumor-Suppressor Gene PLC{delta}1 at 3p22 in Esophageal Squamous Cell Carcinoma Cancer Res., November 15, 2007; 67(22): 10720 - 10726. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Shao, Y. Cui, H. Li, Y. Liu, H. Zhao, Y. Wang, Y. Zhang, K. M. Ng, W. Han, D. Ma, et al. CMTM5 Exhibits Tumor Suppressor Activities and Is Frequently Silenced by Methylation in Carcinoma Cell Lines Clin. Cancer Res., October 1, 2007; 13(19): 5756 - 5762. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Ying, G. Srivastava, W.-S. Hsieh, Z. Gao, P. Murray, S.-K. Liao, R. Ambinder, and Q. Tao The Stress-Responsive Gene GADD45G Is a Functional Tumor Suppressor, with Its Response to Environmental Stresses Frequently Disrupted Epigenetically in Multiple Tumors Clin. Cancer Res., September 15, 2005; 11(18): 6442 - 6449. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Ying, G. Srivastava, Z. Gao, X. Zhang, P. Murray, R. Ambinder, and Q. Tao Promoter hypermethylation of the cyclin-dependent kinase inhibitor (CDKI) gene p21WAF1/CIP1/SDI1 is rare in various lymphomas and carcinomas Blood, January 15, 2004; 103(2): 743 - 746. [Full Text] [PDF]
|
|
|
|
|
|
W. A. Bickmore and S. M. van der Maarel Perturbations of chromatin structure in human genetic disease: recent advances Hum. Mol. Genet., October 15, 2003; 12(90002): R207 - 213. [Abstract] [Full Text] [PDF]
|
|