Transcription-Coupled Events Associating with Immunoglobulin Switch Region Chromatin

Abstract

Class switch recombination (CSR) at the antibody immunoglobulin locus is regulated by germline transcription (GLT)-coupled modifications in the accessibility of the switch region, where CSR takes place. Here we show that histone acetylation of switch regions is linked to CSR but that histone acetylation cannot alone promote CSR or GLT. Activation-induced cytidine deaminase (AID) specifically associates with the CSR target chromatin in a GLT-coupled manner, which may occur potentially by means of physical interaction between AID and the transcription machinery. These data indicate an important role of GLT in the regulation of chromatin accessibility, strongly suggesting that the target of AID is chromatin DNA. Our results give insights on the role of AID and the regulatory mechanism of CSR.

Retinoic acid promotes mouse splenic B cell surface IgG expression and maturation stimulated by CD40 and IL-4

“…Germline transcript expression initiates the process of immunoglobulin (Ig) class switch recombination and therefore is a required step for Ig expression [48]. In our present studies, we first showed that RA markedly reduces stimulation-induced γ1 GLT expression, regardless of the stimuli we used (Fig.…”

“…Although germline Ig gene transcription is understood to be an essential prerequisite step in the process of immunoglobulin gene class switch recombination [48], it is not clear whether quantitative differences in the level of GLT and its persistent expression are physiologically significant. Indeed, we and others have reported that the level of γ1 GLT does not necessarily reflect the level of class switch recombination and subsequent antibody production [29,48,49]. In this study and our previous work [29], a reduction in the expression of γ1 GLT by RA could be detected very early in the B-cell differentiation process (e.g., by 1.5 h in Fig.…”

“…Although RA markedly reduced γ1 GLT expression level, it did not repress, or more or less increased, the levels of Blimp-1 and AID in triple-stimulated B cells, supporting the hypothesis that RA can promote B cell differentiation. It is known that AID and Blimp-1 are responsible for B cell differentiation and/or class switch recombination; especially Blimp-1 gene expression is rapidly up-regulated in B cells that have become terminally differentiated to antibody-secreting cells and plasma cells [48,56]. Under the conditions we have used in our model, such as triple stimulation through CD40, BCR and IL-4, B cells were exposed to several signals known to be important for their activation, therefore, these B cells might go through an early differentiation stage into antibody-producing plasma cells [9,57].…”

Enhanced IgA Class Switching in Marginal Zone and B1 B Cells Relative to Follicular/B2 B Cells

“…When IL-4/IL-5/anti-␦-Dex were also added (10), the two B cell subsets switched to IgA at a similar high frequency between days 3 and 5 of culture ( Class switching to all isotypes occurs by H chain DNA recombination that requires activation-induced cytidine deaminase (AID) (16) and germline transcription through the corresponding switch region DNA (17). This germline transcription likely facilitates the DNA lesion-inducing activity of AID by: 1) promoting chromatin accessibility, 2) AID recruitment via RNA PolII, and 3) generation of a ssDNA target for AID (17)(18)(19). Transcription through the H chain ␣ region is initiated by B cell activation and TGF-␤ signaling (20).…”

Biased dA/dT somatic hypermutation as regulated by the heavy chain intronic iEμ enhancer and 3′Eα enhancers in human lymphoblastoid B cells

“…Instead, it is more likely that trans-factors recruited by iEµ or hs1,2 participate in either the initial targeting or the lesion repairing stages by forming protein complexes with critical factors such as AID or Msh2. The complex formation between RNA polymerase II and AID (Nambu et al, 2003) may be bridged by such a frarasfactor as well. Alternatively, the recruitment of DNA-binding proteins would modify the DNA architecture, thereby making the IgH region more accessible to the SHM machinery, as suggested by iEµ mediated-induction of chromatin conformational alternation (Nikolajczyk et al, 1996(Nikolajczyk et al, , 1999.…”