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A Novel DNMT3B Splice Variant Expressed in Tumor and Pluripotent Cells Modulates Genomic DNA Methylation Patterns and Displays Altered DNA Binding
DNA methylation is an epigenetic mark essential for mammalian development, genomic stability, and imprinting. DNA methylation patterns are established and maintained by three DNA methyltransferases: DNMT1, DNMT3A, and DNMT3B. Interestingly, all three DNMTs make use of alternative splicing. DNMT3B ha...
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Published in: | Molecular cancer research 2009-10, Vol.7 (10), p.1622-1634 |
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Main Authors: | , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | DNA methylation is an epigenetic mark essential for mammalian development, genomic stability, and imprinting. DNA methylation
patterns are established and maintained by three DNA methyltransferases: DNMT1, DNMT3A, and DNMT3B. Interestingly, all three
DNMTs make use of alternative splicing. DNMT3B has nearly 40 known splice variants expressed in a tissue- and disease-specific
manner, but very little is known about the role of these splice variants in modulating DNMT3B function. We describe here the
identification and characterization of a novel alternatively spliced form of DNMT3B lacking exon 5 within the NH 2 -terminal regulatory domain. This variant, which we term DNMT3B3Δ5 because it is closely related in structure to the ubiquitously
expressed DNMT3B3 isoform, is highly expressed in pluripotent cells and brain tissue, is downregulated during differentiation,
and is conserved in the mouse. Creation of pluripotent iPS cells from fibroblasts results in marked induction of DNMT3B3Δ5.
DNMT3B3Δ5 expression is also altered in human disease, with tumor cell lines displaying elevated or reduced expression depending
on their tissue of origin. We then compared the DNA binding and subcellular localization of DNMT3B3Δ5 versus DNMT3B3, revealing
that DNMT3B3Δ5 possessed significantly enhanced DNA binding affinity and displayed an altered nuclear distribution. Finally,
ectopic overexpression of DNMT3B3Δ5 resulted in repetitive element hypomethylation and enhanced cell growth in a colony formation
assay. Taken together, these results show that DNMT3B3Δ5 may play an important role in stem cell maintenance or differentiation
and suggest that sequences encoded by exon 5 influence the functional properties of DNMT3B. (Mol Cancer Res 2009;7(10):1622–34) |
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ISSN: | 1541-7786 1557-3125 |
DOI: | 10.1158/1541-7786.MCR-09-0018 |