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Cell Rep. 2015 Sep 29;12(12):2086-98. doi: 10.1016/j.celrep.2015.08.036. Epub 2015 Sep 10.

DNA Methylation Dynamics of Germinal Center B Cells Are Mediated by AID.

Author information

1
Division of Hematology and Oncology, Weill Cornell Medical College, New York, NY 10065, USA.
2
Division of Hematology and Oncology, Weill Cornell Medical College, New York, NY 10065, USA; Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY 10065, USA.
3
Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY 10065, USA; Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY 10065, USA.
4
IBM Research, Rio de Janeiro 22290-240, Brazil.
5
Epigenomics Core Facility, Weill Cornell Medical College, New York, NY 10065, USA.
6
Immunology Program, Memorial Sloan-Kettering Cancer Center, Gerstner Sloan-Kettering Graduate School, New York, NY 10065, USA.
7
Department of Medicine, The University of Chicago, Chicago, IL 60637, USA.
8
Laboratories of Lymphocyte Biology and Molecular Parasitology, The Rockefeller University, New York, NY 10065, USA.
9
Division of Hematology and Oncology, Weill Cornell Medical College, New York, NY 10065, USA; Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: rshaknovich@gmail.com.

Abstract

Changes in DNA methylation are required for the formation of germinal centers (GCs), but the mechanisms of such changes are poorly understood. Activation-induced cytidine deaminase (AID) has been recently implicated in DNA demethylation through its deaminase activity coupled with DNA repair. We investigated the epigenetic function of AID in vivo in germinal center B cells (GCBs) isolated from wild-type (WT) and AID-deficient (Aicda(-/-)) mice. We determined that the transit of B cells through the GC is associated with marked locus-specific loss of methylation and increased methylation diversity, both of which are lost in Aicda(-/-) animals. Differentially methylated cytosines (DMCs) between GCBs and naive B cells (NBs) are enriched in genes that are targeted for somatic hypermutation (SHM) by AID, and these genes form networks required for B cell development and proliferation. Finally, we observed significant conservation of AID-dependent epigenetic reprogramming between mouse and human B cells.

PMID:
26365193
PMCID:
PMC4591215
DOI:
10.1016/j.celrep.2015.08.036
[Indexed for MEDLINE]
Free PMC Article

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