Epigenetic modifications must underlie lineage-specific differentiation as 
terminally differentiated cells express tissue-specific genes, but their DNA 
sequence is unchanged. Haematopoiesis provides a well-defined model to study 
epigenetic modifications during cell-fate decisions, as multipotent progenitors 
(MPPs) differentiate into progressively restricted myeloid or lymphoid 
progenitors. Although DNA methylation is critical for myeloid versus lymphoid 
differentiation, as demonstrated by the myeloerythroid bias in Dnmt1 hypomorphs, 
a comprehensive DNA methylation map of haematopoietic progenitors, or of any 
multipotent/oligopotent lineage, does not exist. Here we examined 4.6 million 
CpG sites throughout the genome for MPPs, common lymphoid progenitors (CLPs), 
common myeloid progenitors (CMPs), granulocyte/macrophage progenitors (GMPs), 
and thymocyte progenitors (DN1, DN2, DN3). Marked epigenetic plasticity 
accompanied both lymphoid and myeloid restriction. Myeloid commitment involved 
less global DNA methylation than lymphoid commitment, supported functionally by 
myeloid skewing of progenitors following treatment with a DNA methyltransferase 
inhibitor. Differential DNA methylation correlated with gene expression more 
strongly at CpG island shores than CpG islands. Many examples of genes and 
pathways not previously known to be involved in choice between lymphoid/myeloid 
differentiation have been identified, such as Arl4c and Jdp2. Several 
transcription factors, including Meis1, were methylated and silenced during 
differentiation, indicating a role in maintaining an undifferentiated state. 
Additionally, epigenetic modification of modifiers of the epigenome seems to be 
important in haematopoietic differentiation. Our results directly demonstrate 
that modulation of DNA methylation occurs during lineage-specific 
differentiation and defines a comprehensive map of the methylation and 
transcriptional changes that accompany myeloid versus lymphoid fate decisions.