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Comprehensive methylome map of lineage commitment from haematopoietic progenitors

Nature volume 467, pages 338–342 (2010)Cite this article

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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 hypomorphs1, 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.

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Figure 1: Examples of known lineage-related genes showing differential DNA methylation between lymphoid and myeloid progenitors.
Figure 2: Gene expression correlates strongly with DMRs at shores.
Figure 3: CHARM identified genes with previously unknown functions in lymphoid/myeloid lineage commitment and pluripotency maintenance.

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Acknowledgements

We thank L. Jerabek for laboratory management, C. Richter and N. Teja for antibody production, A. Mosley, J. Dollaga and D. Escoto for animal care, E. Zuo and the Stanford PAN facility for microarray processing, and E. Briem and A. N. Allen for CHARM array processing. This investigation was supported by National Institutes of Health grants R37CA053458 and P50HG003233 (to A.P.F), R01AI047457 and R01AI047458 (to I.L.W.), and a grant from the Thomas and Stacey Siebel Foundation (to I.L.W). L.I.R.E. was supported by Special Fellow Career Development award from the Leukemia and Lymphoma Society; J.S. was supported by a fellowship from the California Institute for Regenerative Medicine (T1-00001); D.J.R. was supported by National Institutes of Health grant R00AGO29760; M.A.I. was supported by National Institutes of Health grant CA09151 and a fellowship from the California Institute for Regenerative Medicine (T1-00001); T.S. was supported by a fellowship from the National Institutes of Health (F32AI058521).

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Author notes

  1. Lauren I. R. Ehrlich, Derrick J. Rossi, Thomas Serwold & Holger Karsunky

    Present address: Present addresses: Institute for Cellular and Molecular Biology, Section of Molecular Genetics and Microbiology, University of Texas at Austin, Austin, Texas 78712, USA (L.I.R.E.); Immune Disease Institute, Harvard Stem Cell Institute Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA (D.J.R.); Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, USA (T.S.); Cellant Therapeutics, San Carlos, California 94070, USA (H.K.).,

  2. Hong Ji, Lauren I. R. Ehrlich and Jun Seita: These authors contributed equally to this work.

Authors and Affiliations

  1. Center for Epigenetics and Department of Medicine, Johns Hopkins University School of Medicine, 570 Rangos, 725 N. Wolfe St., Baltimore, Maryland 21205, USA,

    Hong Ji, Peter Murakami, Akiko Doi, Hwajin Lee, Rafael A. Irizarry & Andrew P. Feinberg

  2. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, 94305, California, USA

    Lauren I. R. Ehrlich, Jun Seita, Paul Lindau, Derrick J. Rossi, Matthew A. Inlay, Thomas Serwold, Holger Karsunky, Lena Ho & Irving L. Weissman

  3. Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, 21205, Maryland, USA

    Martin J. Aryee & Rafael A. Irizarry

  4. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, 21231, Maryland, USA

    Martin J. Aryee

  5. Division of Pediatric Hematology/Oncology, Children’s Hospital Boston and Dana Farber Cancer Institute; Division of Hematology, Brigham and Women’s Hospital; Department of Biological Chemistry and Molecular Pharmacology, Stem Cell Transplantation Program, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Harvard Medical School; Harvard Stem Cell Institute,

    Kitai Kim & George Q. Daley

  6. Division of Hematology, Brigham and Women’s Hospital, Boston, 02115, Massachusetts, USA

    Kitai Kim & George Q. Daley

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Contributions

H.J. performed genome-scale and gene-specific DNA methylation analysis; L.I.R.E. and J.S. performed cell-sorting, generated microarray datasets, and performed gene expression analysis; P.L. assisted L.I.R.E. and H.L. assisted H.J.; A.D. and H.J. performed statistical analysis with P.M., M.J.A. and R.A.I; D.J.R., M.A.I., T.S., H.K. and L.H. generated microarray datasets; A.P.F. and I.L.W. designed the experiment, and A.P.F., H.J., L.I.R.E. and J.S. wrote the paper with the assistance of K.K. and G.Q.D.

Corresponding author

Correspondence to Andrew P. Feinberg.

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Competing interests

I.L.W. has stock in Amgen and is co-founder of Cellerant Inc. and Stem Cells Inc. He is also a consultant for Stem Cells Inc. The other authors declare no competing financial interests.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures S1-S7 with legends. Supplementary Table 1-3 were added on 28 September 2010. (PDF 6191 kb)

Supplementary Table 1

This table shows differentially methylated regions identified by CHARM. (XLS 3155 kb)

Supplementary Table 2

This table shows gene ontology functional categories enriched in identified differentially methylated regions. (XLS 357 kb)

Supplementary Table 3

This table shows primer sequences used for bisulfite pyrosequencing and location of CpG sites interrogated. Chromosomal coordinates are based on the UCSC Genome Browser Mouse Feb. 2006 (mm8). (XLS 42 kb)

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Ji, H., Ehrlich, L., Seita, J. et al. Comprehensive methylome map of lineage commitment from haematopoietic progenitors. Nature 467, 338–342 (2010). https://doi.org/10.1038/nature09367

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