Comprehensive methylome map of lineage commitment from haematopoietic progenitors

Abstract

Epigenetic modifications must underlie lineage-specific differentiation as terminally differentiated cells express tissue-specific genes, but their DNA sequence is unchanged. Hematopoiesis 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. While DNA methylation is critical for myeloid versus lymphoid differentiation, as demonstrated by the myeloerythroid bias in Dnmt1 hypomorphs1, a comprehensive DNA methylation map of hematopoietic 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). Dramatic 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, suggesting a role in maintaining an undifferentiated state. Additionally, epigenetic modification of modifiers of the epigenome appears to be important in hematopoietic 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.

DNA methylation profiling in human B cells reveals immune regulatory elements and epigenetic plasticity at Alu elements during B-cell activation

“…3). These results contrast to other differentiation models, where divergent cell fates derived from a multipotent/pluripotent progenitor adopt different epigenetic patterns (Mikkelsen et al 2007;Ji et al 2010). It is possible that a common methylation signature between memory and PCs partially explains the more rapid PC differentiation from memory B cells upon subsequent rechallenge with the same antigen.…”

“…One such epigenetic modification, DNA methylation, occurs on cytosine residues primarily at CpG dinucleotides in mammals. The role of DNA methylation in regulating cellular differentiation from pluripotent and multipotent progenitors has been demonstrated through functional analysis of animals deficient in DNA methyltransferases (DNMTs) (Li et al 1992;Okano et al 1999;Tadokoro et al 2007;Broske et al 2009;, as well as from recent genome-wide studies comparing the DNA methylome of various differentiated cell types and their precursors Lister et al 2009;Ji et al 2010;Hodges et al 2011;Bock et al 2012). In the context of the immune system, mutations in the DNMT3B gene are causal for the development of ICF syndrome (immunodeficiency, centromere instability, and facial anomalies syndrome), a rare autosomal recessive immune disorder (Hansen et al 1999;Xu et al 1999).…”

Epigenetic cancer therapy: rationales, targets and drugs

“…For example, differentiation-associated genes are methylated in mouse and human hematopoietic progenitor cells and become demethylated during differentiation (Ji et al, 2010;Bocker et al, 2011). A functional role of DNA methylation in the differentiation of adult progenitor cells is further supported by the observation that hematopoietic stem cells from mice with reduced DNA methyltransferase 1 activity failed to suppress key differentiation genes and lost their ability to differentiate into lymphoid progeny (Broske et al, 2009).…”

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

“…8 Although hypermethylation of CpG islands within gene promoters has been the main focus of studies on malignant cells, the role of differential DNA methylation in other regions is gaining favor. 9,10 One such region harbors transcriptional enhancers, which reside within noncoding regions of the genome and are known to work over long distances to promote cell/tissue type specific gene expression. Active enhancers are often accompanied by DNA demethylation, 11 and alterations in enhancer methylation are seen in malignant transformation.…”