DNA methyltransferase 1 and DNA methylation patterning contribute to germinal center B-cell differentiation

Publication: Research - peer-reviewJournal article – Annual report year: 2011

  • Author: Shaknovich, Rita

    Weill Cornell Medical College

  • Author: Cerchietti, Leandro

    Weill Cornell Medical College

  • Author: Tsikitas, Lucas

    Weill Cornell Medical College

  • Author: Kormaksson, Matthias

    Weill Cornell Medical College

  • Author: De, Subhajyoti

    Dana-Farber Cancer Institute

  • Author: Figueroa, Maria E.

    Weill Cornell Medical College

  • Author: Ballon, Gianna

    Weill Cornell Medical College

  • Author: Yang, Shao Ning

    Weill Cornell Medical College

  • Author: Weinhold, Nils

    Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark

  • Author: Reimers, Mark

    Virginia Commonwealth University

  • Author: Clozel, Thomas

    Weill Cornell Medical College

  • Author: Luttrop, Karin

    Karolinska Institute

  • Author: Ekstrom, Tomas J.

    Karolinska Institute

  • Author: Frank, Jared

    Weill Cornell Medical College

  • Author: Vasanthakumar, Aparna

    University of Chicago

  • Author: Godley, Lucy A.

    University of Chicago

  • Author: Michor, Franziska

    Dana-Farber Cancer Institute

  • Author: Elemento, Olivier

    Weill Cornell Medical College

  • Author: Melnick, Ari

    Weill Cornell Medical College

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The phenotype of germinal center (GC) B cells includes the unique ability to tolerate rapid proliferation and the mutagenic actions of activation induced cytosine deaminase (AICDA). Given the importance of epigenetic patterning in determining cellular phenotypes, we examined DNA methylation and the role of DNA methyltransferases in the formation of GCs. DNA methylation profiling revealed a marked shift in DNA methylation patterning in GC B cells versus resting/naive B cells. This shift included significant differential methylation of 235 genes, with concordant inverse changes in gene expression affecting most notably genes of the NFkB and MAP kinase signaling pathways. GC B cells were predominantly hypomethylated compared with naive B cells and AICDA binding sites were highly overrepresented among hypomethylated loci. GC B cells also exhibited greater DNA methylation heterogeneity than naive B cells. Among DNA methyltransferases (DNMTs), only DNMT1 was significantly up-regulated in GC B cells. Dnmt1 hypomorphic mice displayed deficient GC formation and treatment of mice with the DNA methyltransferase inhibitor decitabine resulted in failure to form GCs after immune stimulation. Notably, the GC B cells of Dnmt1 hypomorphic animals showed evidence of increased DNA damage, suggesting dual roles for DNMT1 in DNA methylation and double strand DNA break repair.
Original languageEnglish
JournalBlood
Volume118
Issue number13
Pages (from-to)3559-3569
ISSN0006-4971
DOIs
StatePublished - 2011
Peer-reviewedYes
CitationsWeb of Science® Times Cited: 30
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