Comprehensive methylome map of lineage commitment from haematopoietic progenitors

被引：481

作者：

Ji, Hong ^{[1
,2
]}

Ehrlich, Lauren I. R. ^{[3
]}

Seita, Jun ^{[3
]}

Murakami, Peter ^{[1
,2
]}

Doi, Akiko ^{[1
,2
]}

Lindau, Paul ^{[3
]}

Lee, Hwajin ^{[1
,2
]}

Aryee, Martin J. ^{[4
,5
]}

Irizarry, Rafael A. ^{[1
,2
,4
]}

Kim, Kitai ^{[6
,7
,8
,9
,10
]}

Rossi, Derrick J. ^{[3
]}

Inlay, Matthew A. ^{[3
]}

Serwold, Thomas ^{[3
]}

Karsunky, Holger ^{[3
]}

Ho, Lena ^{[3
]}

Daley, George Q. ^{[6
,7
,8
,9
,10
]}

Weissman, Irving L. ^{[3
]}

Feinberg, Andrew P. ^{[1
,2
]}

机构：

[1] Johns Hopkins Univ, Sch Med, Ctr Epigenet, Baltimore, MD 21205 USA

[2] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA

[3] Stanford Univ, Sch Med, Inst Stem Cell Biol & Regenerat Med, Stanford, CA 94305 USA

[4] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD 21205 USA

[5] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21231 USA

[6] Childrens Hosp, Howard Hughes Med Inst, Manton Ctr Orphan Dis Res, Div Pediat Hematol Oncol,Stem Cell Transplantat P, Boston, MA 02115 USA

[7] Dana Farber Canc Inst, Boston, MA 02115 USA

[8] Brigham & Womens Hosp, Div Hematol, Boston, MA 02115 USA

[9] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA

[10] Harvard Stem Cell Inst, Boston, MA 02115 USA

来源：

NATURE | 2010年 / 467卷 / 7313期

基金：

美国国家卫生研究院;

关键词：

DNA METHYLTRANSFERASE; TRANSCRIPTION FACTOR; STEM; METHYLATION; CELLS; MICE; MEIS1;

D O I：

10.1038/nature09367

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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(1), 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.

引用

页码：338 / U120

页数：6

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