Comprehensive methylome map of lineage commitment from haematopoietic progenitors

Hong Ji, Lauren I.R. Ehrlich, Jun Seita, Peter Murakami, Akiko Doi, Paul Lindau, Hwajin Lee, Martin J. Aryee, Rafael A. Irizarry, Kitai Kim, Derrick J. Rossi, Matthew A. Inlay, Thomas Serwold, Holger Karsunky, Lena Ho, George Q. Daley, Irving L. Weissman, Andrew P. Feinberg

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)338-342
Number of pages5
JournalNature
Volume467
Issue number7313
DOIs
StatePublished - Sep 2010

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Comprehensive methylome map of lineage commitment from haematopoietic progenitors'. Together they form a unique fingerprint.

Cite this