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DNA methyltransferase 3B (DNMT3B) mutations in ICF syndrome lead to altered epigenetic modifications and aberrant expression of genes regulating development, neurogenesis and immune function.
- Source :
-
Human molecular genetics [Hum Mol Genet] 2008 Mar 01; Vol. 17 (5), pp. 690-709. Date of Electronic Publication: 2007 Nov 20. - Publication Year :
- 2008
-
Abstract
- Genome-wide DNA methylation patterns are established and maintained by the coordinated action of three DNA methyltransferases (DNMTs), DNMT1, DNMT3A and DNMT3B. DNMT3B hypomorphic germline mutations are responsible for two-thirds of immunodeficiency, centromere instability, facial anomalies (ICF) syndrome cases, a rare recessive disease characterized by immune defects, instability of pericentromeric satellite 2-containing heterochromatin, facial abnormalities and mental retardation. The molecular defects in transcription, DNA methylation and chromatin structure in ICF cells remain relatively uncharacterized. In the present study, we used global expression profiling to elucidate the role of DNMT3B in these processes using cell lines derived from ICF syndrome and normal individuals. We show that there are significant changes in the expression of genes critical for immune function, development and neurogenesis that are highly relevant to the ICF phenotype. Approximately half the upregulated genes we analyzed were marked with low-level DNA methylation in normal cells that was lost in ICF cells, concomitant with loss of repressive histone modifications, particularly H3K27 trimethylation, and gains in transcriptionally active H3K9 acetylation and H3K4 trimethylation marks. In addition, we consistently observed loss of binding of the SUZ12 component of the PRC2 polycomb repression complex and DNMT3B to derepressed genes, including a number of homeobox genes critical for immune system, brain and craniofacial development. We also observed altered global levels of certain histone modifications in ICF cells, particularly ubiquitinated H2AK119. Therefore, this study provides important new insights into the role of DNMT3B in modulating gene expression and chromatin structure and reveals new connections between DNMT3B and polycomb-mediated repression.
- Subjects :
- Abnormalities, Multiple genetics
Acetylation drug effects
Azacitidine analogs & derivatives
Azacitidine pharmacology
B-Lymphocytes cytology
B-Lymphocytes pathology
Case-Control Studies
Cell Line, Transformed
Cell Transformation, Viral
Cells, Cultured
DNA Methylation drug effects
Decitabine
Enzyme Inhibitors pharmacology
Female
Gene Expression Profiling
Genes, Recessive
Histones antagonists & inhibitors
Humans
Hydroxamic Acids pharmacology
Immunologic Deficiency Syndromes pathology
Intellectual Disability genetics
Male
Neurons cytology
Oligonucleotide Array Sequence Analysis
Promoter Regions, Genetic
Time Factors
DNA Methyltransferase 3B
DNA (Cytosine-5-)-Methyltransferases genetics
Epigenesis, Genetic
Gene Expression Regulation, Developmental immunology
Immunologic Deficiency Syndromes genetics
Mutation
Neurons physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2083
- Volume :
- 17
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Human molecular genetics
- Publication Type :
- Academic Journal
- Accession number :
- 18029387
- Full Text :
- https://doi.org/10.1093/hmg/ddm341