Whole-genome fingerprint of the DNA methylome during human B cell differentiation

Abstract

We analyzed the DNA methylome of ten subpopulations spanning the entire B cell differentiation program by whole-genome bisulfite sequencing and high-density microarrays. We observed that non-CpG methylation disappeared upon B cell commitment, whereas CpG methylation changed extensively during B cell maturation, showing an accumulative pattern and affecting around 30% of all measured CpG sites. Early differentiation stages mainly displayed enhancer demethylation, which was associated with upregulation of key B cell transcription factors and affected multiple genes involved in B cell biology. Late differentiation stages, in contrast, showed extensive demethylation of heterochromatin and methylation gain at Polycomb-repressed areas, and genes with apparent functional impact in B cells were not affected. This signature, which has previously been linked to aging and cancer, was particularly widespread in mature cells with an extended lifespan. Comparing B cell neoplasms with their normal counterparts, we determined that they frequently acquire methylation changes in regions already undergoing dynamic methylation during normal B cell differentiation.

Epigenomic Profiling of Human CD4+ T Cells Supports a Linear Differentiation Model and Highlights Molecular Regulators of Memory Development

“…PMD-associated genes generally showed low expression levels compared to FMR-associated genes and were fewer in number ( Figure S2C). We observed a similar segmented loss of global DNA-meth when re-examining DNA-meth profiles from B cells published by the BLUEPRINT consortium (Kulis et al, 2015). Here too, PMDs were the genomic segments that displayed progressive loss of DNA-meth with differentiation into memory B cells and antibody-secreting plasma cells ( Figure 1D), indicating that this phenomenon is shared during lymphocyte development.…”

DNA Methylation in Cancer and Aging

“…Low-level de novo methylation of CpG islands is known to take place in normal tissues and has been shown to increase with age (6,11,12). In a similar manner, it has been shown that many of the general demethylation events observed in tumors also take place in normal cells (13), and this can even be seen in aging hematopoietic stem cells (HSC) and epidermal stem cells in vivo (14,15).…”

“…Interestingly, several studies have already established that hematopoietic stem cells from both mouse and man actually undergo a natural aging process whereby they increase in number while their lymphoid differentiation capacity is diminished, leading to a myeloid-dominant phenotype (34). Whole-genome bisulfite analysis indicates that this aging process is associated with typical de novo and demethylation events normally found in tumors (6,14), and there is a good possibility that these alterations in methylation actually play a role in promoting stem cell renewal and inhibiting differentiation. Strikingly, the changes in DNA methylation seen in aging stem cells are very similar to those detected in MDS (14), strongly suggesting that a large part of the "abnormal" methylation profile seen in this disease probably comes about as a natural result of aging even in the absence of genome mutations.…”

Is Cellular Heterogeneity Merely a Confounder to be Removed from Epigenome-Wide Association Studies?

“…However, some have attempted to measure only DNA methylation differences that are not due to cellular heterogeneity, by deriving samples with as pure a cell type as possible. For example, blood can be fractionated and DNA methylation investigated in specific cell types [32][33][34][35]. However, even relatively 'pure' populations of cells, such as CD4 + T cells, actually comprise many functionally and epigenetically distinct cell subpopulations (Th1, Th2, Th17, Treg, etc.).…”