A global DNA methylation and gene expression analysis of early human B-cell development reveals a demethylation signature and transcription factor network

Abstract

The epigenetic changes during B-cell development relevant to both normal function and hematologic malignancy are incompletely understood. We examined DNA methylation and RNA expression status during early B-cell development by sorting multiple replicates of four separate stages of pre-B cells derived from normal human fetal bone marrow and applied high-dimension DNA methylation scanning and expression arrays. Features of promoter and gene body DNA methylation were strongly correlated with RNA expression in multipotent progenitors (MPPs) both in a static state and throughout differentiation. As MPPs commit to pre-B cells, a predominantly demethylating phenotype ensues, with 79% of the 2966 differentially methylated regions observed involving demethylation. Demethylation events were more often gene body associated rather than promoter associated; predominantly located outside of CpG islands; and closely associated with EBF1, E2F, PAX5 and other functional transcription factor (TF) sites related to B-cell development. Such demethylation events were accompanied by TF occupancy. After commitment, DNA methylation changes appeared to play a smaller role in B-cell development. We identified a distinct development-dependent demethylation signature which has gene expression regulatory properties for pre-B cells, and provide a catalog reference for the epigenetic changes that occur in pre-B-cell leukemia and other B-cell-related diseases.

Effect of prenatal arsenic exposure on DNA methylation and leukocyte subpopulations in cord blood

“…Thus, the upstream epigenetic alteration could only be revealed upon more detailed examination of the blood. [39][40][41][42] Our agnostic approach identified several genes and biological pathways containing CpG sites that were differentially methylated in relationship to increasing prenatal arsenic exposure. While our study did not examine gene expression, it is noteworthy that many toxicological studies report arsenic interacting with many of these same genes and biological pathways.…”

Integrated methylome and transcriptome analysis reveals novel regulatory elements in pediatric acute lymphoblastic leukemia

“…Increasing gene body methylation along with promoter methylation has been shown to have a stronger repressive effect on gene expression during normal B-cell development than promoter methylation alone. 18 However, the effect of gene body methylation in the absence of promoter methylation is less clear. Both inverse and positive correlations between gene body methylation and gene expression were observed.…”

The DNA methylation profile of activated human natural killer cells

“…DNA methylation is thought to provide a chemically stable mark that serves to initiate and reinforce these cell fate decisions. 2 Large-scale methylation studies of specific lineage pathways have been performed on differentiating erythroid, 3,4 T lymphocyte, 5,6 B lymphocyte, 7 and myeloid 4 cells. These important developmental studies reveal insights into the regulation of cell fate decisions but also serve as a potential source of biomarkers that help characterize different immune compartments during the immune response.…”