S-S synapsis during class switch recombination is promoted by distantly located transcriptional elements and activation-induced deaminase.
Molecular mechanisms underlying synapsis of activation-induced deaminase (AID)-targeted S regions during class switch recombination (CSR) are poorly understood. By using chromosome conformation capture techniques, we found that in B cells, the Emicro and 3'Ealpha enhancers were in close spatial proximity, forming a unique chromosomal loop configuration. B cell activation led to recruitment of the germline transcript (GLT) promoters to the Emicro:3'Ealpha complex in a cytokine-dependent fashion. This structure facilitated S-S synapsis because Smicro was proximal to Emicro and a downstream S region was corecruited with the targeted GLT promoter to Emicro:3'Ealpha. We propose that GLT promoter association with the Emicro:3'Ealpha complex creates an architectural scaffolding that promotes S-S synapsis during CSR and that these interactions are stabilized by AID. Thus, the S-S synaptosome is formed as a result of the self-organizing transcription system that regulates GLT expression and may serve to guard against spurious chromosomal translocations.
Wuerffel
Robert
R
Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, IL 60612-7344, USA.
Wang
Lili
L
Grigera
Fernando
F
Manis
John
J
Selsing
Erik
E
Perlot
Thomas
T
Alt
Frederick W
FW
Cogne
Michel
M
Pinaud
Eric
E
Kenter
Amy L
AL
D000818:Animals; D002478:Cells, Cultured; D023902:Chromosome Pairing / Q000235:genetics*; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism; D005434:Flow Cytometry; D050438:Genes, Immunoglobulin Heavy Chain; D017578:Immunoglobulin Class Switching / Q000235:genetics*; D007134:Immunoglobulin Switch Region / Q000235:genetics*; D008213:Lymphocyte Activation / Q000235:genetics*; D051379:Mice; D050436:Regulatory Elements, Transcriptional / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase