Human Molecular Genetics Advance Access originally published online on November 20, 2007
Human Molecular Genetics 2008 17(5):690-709; doi:10.1093/hmg/ddm341
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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
1 Department of Biochemistry and Molecular Biology, UF Shands Cancer Center Program in Cancer Genetics, Epigenetics, and Tumor Virology, University of Florida, PO Box 100245, Gainesville, FL 32610, USA 2 Cancer Epigenetics Laboratory, State Key Laboratory in Oncology in South China, Sir YK Pao Center for Cancer, Department of Clinical Oncology, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong 3 Johns Hopkins Singapore, Biopolis, Singapore 4 Laboratory of Functional Genomics, Institute of Molecular and Cell Biology, Proteos, Singapore 138673 5 Department of Internal Medicine, Wayne State University, Detroit, MI 48201 USA and 6 Department of Pathology, University of Florida, PO Box 100245, Gainesville, FL 32610, USA
* To whom correspondence should be addressed at: Department of Biochemistry and Molecular Biology, University of Florida, College of Medicine Box 100245, 1600 S.W. Archer Rd. Gainesville, FL 32610 USA. Tel: +1 3523921810; Fax: +1 3523922953; Email: keithr{at}ufl.edu
Received September 7, 2007; Accepted November 16, 2007
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.
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