A global DNA methylation and gene expression analysis of early human B-cell development reveals a demethylation signature and transcription factor network.
Nucleic Acids Res, 2012/12;40(22):11339-51.
Lee ST[1], Xiao Y, Muench MO, Xiao J, Fomin ME, Wiencke JK, Zheng S, Dou X, de Smith A, Chokkalingam A, Buffler P, Ma X, Wiemels JL
Affiliations
PMID: 23074194DOI: 10.1093/nar/gks957
Impact factor: 19.16
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.
MeSH terms
B-Lymphocytes; DNA Methylation; Gene Expression Profiling; Gene Expression Regulation, Developmental; Gene Regulatory Networks; Humans; Multipotent Stem Cells; Precursor Cells, B-Lymphoid; RNA; Transcription Factors
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