Regulation of AID expression in the immune response.
The B cell-specific enzyme activation-induced cytidine deaminase (AID) has been shown to be essential for isotype switching and affinity maturation of antibody genes during the immune response. Conversely, AID activity has also been linked to autoimmunity and tumorigenesis. Determining how AID expression is regulated in vivo is therefore central to understanding its role in health and disease. Here we use phylogenetic footprinting and high-resolution histone acetylation mapping to accurately demarcate AID gene regulatory boundaries. Based on this strategy, we identify a novel, positive regulatory element required for AID transcription. Furthermore, we generate two AID indicator mouse strains using bacterial artificial chromosomes that faithfully recapitulate endogenous AID expression. The first strain uses a green fluorescent protein reporter to identify B cells that actively express AID during the immune response. In the second strain, AID transcription affects the permanent expression of a yellow fluorescent protein reporter in post-germinal center and terminally differentiated lymphocytes. We demonstrate the usefulness of these novel strains by resolving recent contradictory observations on AID expression during B cell ontogeny.
Crouch
Elizabeth E
EE
Genomic Integrity and Immunity, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Li
Zhiyu
Z
Takizawa
Makiko
M
Fichtner-Feigl
Stefan
S
Gourzi
Polyxeni
P
Montaño
Carolina
C
Feigenbaum
Lionel
L
Wilson
Patrick
P
Janz
Siegfried
S
Papavasiliou
F Nina
FN
Casellas
Rafael
R
D000107:Acetylation; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D001483:Base Sequence; D022202:Chromosomes, Artificial, Bacterial; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism*; D018983:DNA Footprinting; D004252:DNA Mutational Analysis; D017931:DNA Primers; D003850:Deoxyribonuclease I / Q000378:metabolism; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology*; D006657:Histones / Q000378:metabolism; D007111:Immunity, Cellular / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D010802:Phylogeny; D050436:Regulatory Elements, Transcriptional / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D017931:DNA Primers; D006657:Histones; D003850:Deoxyribonuclease I; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase