A global DNA methylation and gene expression analysis of early human B-cell development reveals a demethylation signature and transcription factor network.
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.
Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA 94158, USA.
Seung-Tae
ST
Lee
Yuanyuan
Y
Xiao
Marcus O
MO
Muench
Jianqiao
J
Xiao
Marina E
ME
Fomin
John K
JK
Wiencke
Shichun
S
Zheng
Xiaoqin
X
Dou
Adam
A
de Smith
Anand
A
Chokkalingam
Patricia
P
Buffler
Xiaomei
X
Ma
Joseph L
JL
Wiemels
D001402:B-Lymphocytes / Q000378:metabolism*; D019175:DNA Methylation; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D006801:Humans; D039902:Multipotent Stem Cells / Q000378:metabolism; D054448:Precursor Cells, B-Lymphoid / Q000378:metabolism*; D012313:RNA / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*
D014157:Transcription Factors; D012313:RNA