Quiescent lymphocytes are known to undergo rapid clonal expansion and differentiation upon encountering foreign antigen. During this activation process lymphocytes experience drastic morphological and transcriptional changes. However, how such rapid changes are regulated remain uncharacterised, especially in the context of genome architecture.
Recent advances in understanding the 3D structure of chromosomes has led to increased focus on the role of genome architecture in regulating gene transcription. For instance, distal DNA element like enhancer can form loop with promoter to drive gene transcription and these three-dimensional structures have been shown to be lineage specific and are thus very critical in regulating transcription.
Here, to study how genome architecture was altered during division-linked antibody-secreting cell development, naïve B lymphocytes were stimulated with LPS and genome organisation was studied at different stages of the process using genome wide chromosome conformation capture (Hi-C) and RNA-sequencing.
RNA-seq revealed a large transcriptional burst as early as 3 hr post-stimulation and a transcription landscape that was very dynamically altered throughout the activation and differentiation process.
In contrast, the genome architecture exhibited minimal changes early but abruptly re-organised just prior to the first cell division. Surprisingly, this three-dimensional structure stayed unaltered during the clonal expansion for 4 days, not until when they differentiated into plasmablast in another restructuring event.
With the utilisation of FUCCI mouse system to indicate the cell cycle stage, it is further demonstrated that the genome architecture undergoes reorganisation prior to S phase, which suggests that the genome can restructure independent of DNA synthesis.
Overall, this suggests the genome architecture of B cells, unlike transcription, exhibits two discrete waves of restructuring events to firstly support clonal expansion and then differentiation into antibody-secreting cells, and the very first wave of restructuring event occurs independent of cell division and DNA synthesis.