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Proc Natl Acad Sci U S A. 2014 Dec 30;111(52):18667-72. doi: 10.1073/pnas.1420575111. Epub 2014 Dec 15.

Epigenetic targeting of activation-induced cytidine deaminase.

Author information

1
Laboratory of Molecular Immunology.
2
Genomics & Immunity, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
3
Laboratory of Molecular Immunology, Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065; and nussen@rockefeller.edu drobbiani@rockefeller.edu.
4
Laboratory of Molecular Immunology, nussen@rockefeller.edu drobbiani@rockefeller.edu.

Abstract

Activation-induced cytidine deaminase (AID) initiates class switch recombination (CSR) and somatic hypermutation (SHM) by deaminating cytosine residues in immunoglobulin genes (Igh, Igκ, and Igλ). At a lower frequency, AID also causes collateral DNA damage at non-Ig loci, including genes that are rearranged or mutated in B-cell lymphoma. Precisely how AID is recruited to these off-target sites is not entirely understood. To gain further insight into how AID selects its targets, we compared AID-mediated translocations in two different cell types, B cells and mouse embryonic fibroblasts (MEFs). AID targets a distinct set of hotspots in the two cell types. In both cases, hotspots are concentrated in highly transcribed but stalled genes. However, transcription alone is insufficient to recruit AID activity. Comparison of genes similarly transcribed in B cells and MEFs but targeted in only one of the two cell types reveals a common set of epigenetic features associated with AID recruitment in both cells. AID target genes are enriched in chromatin modifications associated with active enhancers (such as H3K27Ac) and marks of active transcription (such as H3K36me3) in both fibroblasts and B cells, indicating that these features are universal mediators of AID recruitment.

KEYWORDS:

active enhancer; chromosome translocation; lymphoma; mouse embryonic fibroblast; transcription elongation

PMID:
25512519
PMCID:
PMC4284578
DOI:
10.1073/pnas.1420575111
[Indexed for MEDLINE]
Free PMC Article

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