3D chromosomal architecture in germinal center B cells and its alterations in lymphomagenesis

Abstract

In eukaryotic cells, the genome is three dimensionally (3D) organized with DNA interaction dynamics and topology changes that regulate gene expression and drive cell fate. Upon antigen stimulation, naive B cells are activated and form germinal centers (GC) for the generation of memory B cells and plasma cells. Thereby, terminal B-cell differentiation and associated humoral immune response require massive but rigorous 3D DNA reorganization. Here, we review the dynamics of genome reorganization during GC formation and the impact of its alterations on lymphomagenesis from the nucleosome structure to the higher order chromosome organization. We particularly discuss the identified architects of 3D DNA in GC B cells and the role of their mutations in B-cell lymphomas.

Figure 1

Graphical representation of GC identity establishment by OCT2-OCAB-MEF2B. OCT2 is ‘pre-positioned’ at latent GC enhancers and superenhancers in naive B cells, and de novo GC OCT2 BS are not accessible at this stage. Expression of OCAB in B cells transitioning to the GC reaction results in its binding to OCT2, with subsequent increase in chromatin accessibility. This in turn opens additional canonical and non-canonical OCT2 BS (de novo GC OCT2 BS) for further binding and chromatin opening by these complexes and the formation of GC-specific superenhancers. The further expression of MEF2B in GC B cells results in the formation of OCT2-OCAB-MEF2B ternary complexes, specifically at the key superenhancer subunits most essential for EPIs and GC B cells, which is further supported by OCAB recruitment of the mediator complex. Loss of OCAB reverses this process and leads to loss of accessibility at GC enhancers and loss of expression of GC-specific genes.

Figure 2

Graphical representation of chromatin architecture regulatory protein alterations in GC-derived lymphomas. The genome ranges from highly compacted to decompacted through three continuous compartments (B to I to A). These are associated with histone marks that either silence (H3K9me3 and H3K27me3) or facilitate activation (H3K36me2) of gene expression. The gradient of H1 density is associated with the range of chromatin compaction and hence epigenetic and transcriptional activation potential. H1 loss of function mutations lead to decompaction and activation of embryonic stem cell genes. Cohesin complexes create chromatin loops such as EPIs. SMC3 haploinsufficiency impairs GC B-cell differentiation by reducing such EPIs at GC exit genes and tumor suppressors thus contributing to lymphomagenesis. BAF subunits are involved in nucleosome ejection and repositioning and are frequently mutated in GC lymphomas. Their precise role in lymphomagenesis still needs to be clarified, but recent studies suggest that BAF components have a tumor suppressor role [30]. Histone H1 proteins are represented in purple, H3 post-modifications by dots: H3K9me3 (black), H3K27me3 (red), H3K36me2 (green), H3K27ac (orange) and lightning indicate alterations of chromatin regulatory proteins and histones.