title: Inactive DNMT3B splice variants modulate de novo DNA methylation.
abstract: Inactive DNA methyltransferase (DNMT) 3B splice isoforms are associated with changes in DNA methylation, yet the mechanisms by which they act remain largely unknown. Using biochemical and cell culture assays, we show here that the inactive DNMT3B3 and DNMT3B4 isoforms bind to and regulate the activity of catalytically competent DNMT3A or DNMT3B molecules. DNMT3B3 modestly stimulated the de novo methylation activity of DNMT3A and also counteracted the stimulatory effects of DNMT3L, therefore leading to subtle and contrasting effects on activity. DNMT3B4, by contrast, significantly inhibited de novo DNA methylation by active DNMT3 molecules, most likely due to its ability to reduce the DNA binding affinity of co-complexes, thereby sequestering them away from their substrate. Immunocytochemistry experiments revealed that in addition to their effects on the intrinsic catalytic function of active DNMT3 enzymes, DNMT3B3 and DNMT34 drive distinct types of chromatin compaction and patterns of histone 3 lysine 9 tri-methylation (H3K9me3) deposition. Our findings suggest that regulation of active DNMT3 members through the formation of co-complexes with inactive DNMT3 variants is a general mechanism by which DNMT3 variants function. This may account for some of the changes in DNA methylation patterns observed during development and disease.
authors.affiliation: Department of Molecular and Cellular Biology, University of California Davis, Davis, California, United States of America.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Gordon
authors.forename: Stella R
authors.initials: SR
authors.lastname: Hartono
authors.forename: Frédéric
authors.initials: F
authors.lastname: Chédin
mesh_terms: D000818:Animals; D002460:Cell Line; D002843:Chromatin; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D020868:Gene Silencing; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D011485:Protein Binding; D020033:Protein Isoforms; D012326:RNA Splicing; D000097584:DNA Methyltransferase 3B
chemical_list: D002843:Chromatin; D004248:DNA (Cytosine-5-)-Methyltransferases; D006657:Histones; D020033:Protein Isoforms; D000097584:DNA Methyltransferase 3B
references.citation: Hum Mol Genet. 2009 Sep 1;18(17):3178-93
references.pmid: 19482874
references.citation: Nucleic Acids Res. 2004 May 17;32(9):2716-29
references.pmid: 15148359
references.citation: Development. 2006 Mar;133(6):1183-92
references.pmid: 16501171
references.citation: Oncogene. 2005 Nov 3;24(48):7213-23
references.pmid: 16170379
references.citation: Proc Natl Acad Sci U S A. 2002 Jul 23;99(15):10060-5
references.pmid: 12110732
references.citation: Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):16916-21
references.pmid: 12481029
references.citation: Mol Cell Biol. 2003 Aug;23(16):5594-605
references.pmid: 12897133
references.citation: Nat Genet. 1998 Jul;19(3):219-20
references.pmid: 9662389
references.citation: J Cell Biochem. 2005 Aug 1;95(5):902-17
references.pmid: 15861382
references.citation: Oncogene. 2003 Jul 24;22(30):4723-33
references.pmid: 12879017
references.citation: Histochem Cell Biol. 2006 Jan;125(1-2):91-102
references.pmid: 16231189
references.citation: Mol Cancer Res. 2004 Jan;2(1):62-72
references.pmid: 14757847
references.citation: Nature. 2007 Dec 6;450(7171):908-12
references.pmid: 17994007
references.citation: Mol Cancer Res. 2009 Oct;7(10):1622-34
references.pmid: 19825994
references.citation: Gene. 1999 Aug 5;236(1):87-95
references.pmid: 10433969
references.citation: J Biol Chem. 2006 Sep 8;281(36):25893-902
references.pmid: 16829525
references.citation: Mol Cell Biol. 2003 Apr;23(7):2577-86
references.pmid: 12640138
references.citation: Nature. 2007 Sep 13;449(7159):248-51
references.pmid: 17713477
references.citation: Nucleic Acids Res. 2005 Jan 13;33(1):307-15
references.pmid: 15653631
references.citation: J Biol Chem. 2010 Sep 17;285(38):29091-100
references.pmid: 20630873
references.citation: Hum Mol Genet. 2008 Mar 1;17(5):690-709
references.pmid: 18029387
references.citation: Science. 2002 Sep 13;297(5588):1807-8; discussion 1807-8
references.pmid: 12229925
references.citation: J Mol Biol. 1967 Jun 14;26(2):365-9
references.pmid: 4291934
references.citation: Nucleic Acids Res. 2011 Jul;39(12):4984-5002
references.pmid: 21378119
references.citation: Prog Mol Biol Transl Sci. 2011;101:255-85
references.pmid: 21507354
references.citation: Nucleic Acids Res. 2001 Sep 1;29(17):3506-12
references.pmid: 11522819
references.citation: Cancer Res. 2010 Jul 15;70(14):5840-50
references.pmid: 20587527
references.citation: PLoS Genet. 2010 Sep 09;6(9):e1001106
references.pmid: 20838592
references.citation: Chembiochem. 2011 Jan 24;12(2):206-22
references.pmid: 21243710
references.citation: Epigenetics. 2010 Apr;5(3):229-40
references.pmid: 20305384
references.citation: Arch Biochem Biophys. 2010 Jun 1;498(1):13-22
references.pmid: 20227382
references.citation: Cancer Res. 2006 Sep 1;66(17):8361-6
references.pmid: 16951144
references.citation: Mol Cell Biol. 2004 Oct;24(20):9048-58
references.pmid: 15456878
references.citation: Nucleic Acids Res. 1999 Jun 1;27(11):2291-8
references.pmid: 10325416
references.citation: Oncogene. 2007 Aug 16;26(38):5553-63
references.pmid: 17353906
references.citation: Nature. 2006 Jul 20;442(7100):312-6
references.pmid: 16732292
references.citation: J Mol Biol. 2011 Jun 24;409(5):758-72
references.pmid: 21549127
references.citation: Biochemistry. 2004 Sep 14;43(36):11460-73
references.pmid: 15350132
references.citation: J Biol Chem. 2002 Aug 2;277(31):28176-81
references.pmid: 12015329
references.citation: Mol Reprod Dev. 2004 Mar;67(3):323-36
references.pmid: 14735494
references.citation: J Biol Chem. 2004 Jun 25;279(26):27816-23
references.pmid: 15105426
references.citation: Annu Rev Biochem. 2005;74:481-514
references.pmid: 15952895
references.citation: Biochem Cell Biol. 2005 Aug;83(4):438-48
references.pmid: 16094447