Figure 7.

Model for how the PTIP–PA1 subcomplex promotes transcription for IgH class switching independently from the associated MLL3/MLL4 complex. Prior to stimulation, Igh-μ germline transcripts are produced from the 5′ Eμ region, and a full-length Igh transcript is produced from upstream of the V(D)J gene segment. PTIP and PA1 proteins stabilize each other in a constitutive subcomplex that, upon B-cell activation, localizes to downstream Igh-γ switch regions through an unknown transcription factor interaction, where it then interacts with the transcription machinery (i.e., a chromatin-modifying complex or polymerase II [Pol II]) to promote germline transcription initiation (step 1). The Igh-γ3 switch region is shown as an example. Dashed arrows indicate a direct or indirect association. H3K4me3 marks are deposited by a Set1-like methyltransferase either before or after transcription initiation (step 2). AID is targeted to the now accessible chromatin at the switch regions, leading to DSB formation (step 3). DSBs are repaired by the NHEJ pathway and the 53BP1 and RIF1 DDR factors, leading to a recombined Igh locus and expression of IgG3 (step 4). Constant (C) region exons are indicated by blue rectangles, switch regions are indicated by pink ovals, the 5′ enhancer is indicated by an orange oval, and the black rectangle indicates the antigen recognition V(D)J gene segment. Cγ3, Cδ, and Cμ refer to immunoglobulins IgG, IgD, and IgM, respectively.