Epigenetics of antigen-receptor gene assembly

Abstract

The antigen receptor genes are organized into distinct DNA elements that encode the variable (V), diversity (D) and joining (J) regions. It is now well established that the rearrangement of antigen receptor genes is regulated by developmental-specific modulation of chromatin structure. Further studies involving statistical mechanics should provide physical insight into the physical mechanisms that underlie the association of antigen receptor gene segments.

Figure 1

(A) Diagram depicting B cell development. Ig D_HJ_H and V_HD_HJ_H gene rearrangements are indicated. Transcriptional regulators controlling distinct checkpoints during B-lineage maturation are shown. (B) Diagram depicting T-lineage development. TCR gene rearrangements are indicated. Notch signaling and transcriptional regulators controlling distinct checkpoints during T-lineage maturation are shown.

Figure 2

(A) Regulatory network controlling B-lineage specification and commitment is shown. (B) Regulatory network controlling T-lineage development is indicated.

Figure 3

Spectrum of Igh and Igl topologies and nuclear location in pre-pro-B, pro-B and pre-B cells. Indicated are the nuclear membrane localization of the Igh and Igl loci in pro-B cells. Igh locus contraction is observed on both alleles in pro-B cells, presumably mediated by looping of the intervening sequences. Mono-allelic looping bringing the Igh V, D and J elements into close proximity has been observed at the pro--B cells but not at the pre-pro-B cell stage. The IgL loci are also proposed to undergo mono-allelic looping (note that this still has to be demonstrated).