Charting the dynamic epigenome during B-cell development.

The epigenetic landscape undergoes a widespread modulation during embryonic development and cell differentiation. Within the hematopoietic system, B cells are perhaps the cell lineage with a more dynamic DNA methylome during their maturation process, which involves approximately one third of all the CpG sites of the genome. Although each B-cell maturation step displays its own DNA methylation fingerprint, the DNA methylome is more extensively modified in particular maturation transitions. These changes are gradually accumulated in specific chromatin environments as cell differentiation progresses and reflect different features and functional states of B cells. Promoters and enhancers of B-cell transcription factors acquire activation-related epigenetic marks and are sequentially expressed in particular maturation windows. These transcription factors further reconfigure the epigenetic marks and activity state of their target sites to regulate the expression of genes related to B-cell functions. Together with this observation, extensive DNA methylation changes in areas outside gene regulatory elements such as hypomethylation of heterochromatic regions and hypermethylation of CpG-rich regions, also take place in mature B cells, which intriguingly have been described as hallmarks of cancer. This process starts in germinal center B cells, a highly proliferative cell type, and becomes particularly apparent in long-lived cells such as memory and plasma cells. Overall, the characterization of the DNA methylome during B-cell differentiation not only provides insights into the complex epigenetic network of regulatory elements that mediate the maturation process but also suggests that late B cells also passively accumulate epigenetic changes related to cell proliferation and longevity.