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Comprehensive methylome map of lineage commitment from haematopoietic progenitors

Naturevolume 467, pages338–342 (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 inDnmt1 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 asArl4c andJdp2. Several transcription factors, includingMeis1, 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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References

  1. Bröske, A. M. et al. DNA methylation protects hematopoietic stem cell multipotency from myeloerythroid restriction.Nature Genet.41, 1207–1215 (2009)

    Article  Google Scholar 

  2. Chao, M. P., Seita, J. & Weissman, I. L. Establishment of a normal hematopoietic and leukemia stem cell hierarchy.Cold Spring Harb. Symp. Quant. Biol.73, 439–449 (2008)

    Article CAS  Google Scholar 

  3. Trowbridge, J. J., Snow, J. W., Kim, J. & Orkin, S. H. DNA methyltransferase 1 is essential for and uniquely regulates hematopoietic stem and progenitor cells.Cell Stem Cell5, 442–449 (2009)

    Article CAS  Google Scholar 

  4. Gardiner-Garden, M. & Frommer, M. CpG islands in vertebrate genomes.J. Mol. Biol.196, 261–282 (1987)

    Article CAS  Google Scholar 

  5. Irizarry, R. A. et al. Comprehensive high-throughput arrays for relative methylation (CHARM).Genome Res.18, 780–790 (2008)

    Article CAS  Google Scholar 

  6. Doi, A. et al. Differential methylation of tissue- and cancer-specific CpG island shores distinguishes human induced pluripotent stem cells, embryonic stem cells and fibroblasts.Nature Genet.41, 1350–1353 (2009)

    Article CAS  Google Scholar 

  7. Irizarry, R. A. et al. The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores.Nature Genet.41, 178–186 (2009)

    Article CAS  Google Scholar 

  8. Molina, T. J. et al. Profound block in thymocyte development in mice lacking p56lck.Nature357, 161–164 (1992)

    Article CAS ADS  Google Scholar 

  9. Klebanoff, S. J. Myeloperoxidase: friend and foe.J. Leukoc. Biol.77, 598–625 (2005)

    Article CAS  Google Scholar 

  10. Cacalano, G. et al. Neutrophil and B cell expansion in mice that lack the murine IL-8 receptor homolog.Science265, 682–684 (1994)

    Article CAS ADS  Google Scholar 

  11. Gupta, S. K., Gupta, M., Hoffman, B. & Liebermann, D. A. Hematopoietic cells from gadd45a-deficient and gadd45b-deficient mice exhibit impaired stress responses to acute stimulation with cytokines, myeloablation and inflammation.Oncogene25, 5537–5546 (2006)

    Article CAS  Google Scholar 

  12. Barreto, G. et al. Gadd45a promotes epigenetic gene activation by repair-mediated DNA demethylation.Nature445, 671–675 (2007)

    Article CAS  Google Scholar 

  13. Rai, K. et al. DNA demethylation in zebrafish involves the coupling of a deaminase, a glycosylase, and Gadd45.Cell135, 1201–1212 (2008)

    Article CAS  Google Scholar 

  14. Engel, N. et al. Conserved DNA methylation inGadd45a−/− mice.Epigenetics4, 98–99 (2009)

    Article CAS  Google Scholar 

  15. Bell, J. J. & Bhandoola, A. The earliest thymic progenitors for T cells possess myeloid lineage potential.Nature452, 764–767 (2008)

    Article CAS ADS  Google Scholar 

  16. Wada, H. et al. Adult T-cell progenitors retain myeloid potential.Nature452, 768–772 (2008)

    Article CAS ADS  Google Scholar 

  17. Wei, S. M., Xie, C. G., Abe, Y. & Cai, J. T. ADP-ribosylation factor like 7 (ARL7) interacts with α-tubulin and modulates intracellular vesicular transport.Biochem. Biophys. Res. Commun.384, 352–356 (2009)

    Article CAS  Google Scholar 

  18. Chadwick, K., Shojaei, F., Gallacher, L. & Bhatia, M. Smad7 alters cell fate decisions of human hematopoietic repopulating cells.Blood105, 1905–1915 (2005)

    Article CAS  Google Scholar 

  19. King, A. G., Kondo, M., Scherer, D. C. & Weissman, I. L. Lineage infidelity in myeloid cells with TCR gene rearrangement: a latent developmental potential of proT cells revealed by ectopic cytokine receptor signaling.Proc. Natl Acad. Sci. USA99, 4508–4513 (2002)

    Article CAS ADS  Google Scholar 

  20. Kondo, M. et al. Cell-fate conversion of lymphoid-committed progenitors by instructive actions of cytokines.Nature407, 383–386 (2000)

    Article CAS ADS  Google Scholar 

  21. Jin, C. et al. Regulation of histone acetylation and nucleosome assembly by transcription factor JDP2.Nature Struct. Mol. Biol.13, 331–338 (2006)

    Article CAS  Google Scholar 

  22. Popov, V. M. et al. TheDachshund gene in development and hormone-responsive tumorigenesis.Trends Endocrinol. Metab.21, 41–49 (2010)

    Article CAS  Google Scholar 

  23. Pillay, L. M., Forrester, A. M., Erickson, T., Berman, J. N. & Waskiewicz, A. J. The Hox cofactors Meis1 and Pbx act upstream ofgata1 to regulate primitive hematopoiesis.Dev. Biol.340, 306–317 (2010)

    Article CAS  Google Scholar 

  24. Hu, Y. L., Fong, S., Ferrell, C., Largman, C. & Shen, W. F. HOXA9 modulates its oncogenic partnerMeis1 to influence normal hematopoiesis.Mol. Cell. Biol.29, 5181–5192 (2009)

    Article CAS  Google Scholar 

  25. Crable, S. C. & Anderson, K. P. A. PAR domain transcription factor is involved in the expression from a hematopoietic-specific promoter for the humanLMO2 gene.Blood101, 4757–4764 (2003)

    Article CAS  Google Scholar 

  26. Du, Y., Jenkins, N. A. & Copeland, N. G. Insertional mutagenesis identifies genes that promote the immortalization of primary bone marrow progenitor cells.Blood106, 3932–3939 (2005)

    Article CAS  Google Scholar 

  27. Tadokoro, Y., Ema, H., Okano, M., Li, E. & Nakauchi, H. De novo DNA methyltransferase is essential for self-renewal, but not for differentiation, in hematopoietic stem cells.J. Exp. Med.204, 715–722 (2007)

    Article CAS  Google Scholar 

  28. Claus, R., Almstedt, M. & Lubbert, M. Epigenetic treatment of hematopoietic malignancies:in vivo targets of demethylating agents.Semin. Oncol.32, 511–520 (2005)

    Article CAS  Google Scholar 

  29. Feinberg, A. P. & Irizarry, R. A. Evolution in Health and Medicine Sackler Colloquium: stochastic epigenetic variation as a driving force of development, evolutionary adaptation, and disease.Proc. Natl Acad. Sci. USA107, 1757–1764 (2005)

    Article ADS  Google Scholar 

  30. Kim, K. et al. Epigenetic memory in induced pluripotent stem cells.Nature advance online publication, 10.1038/nature09342 (19 July 2010)

Download references

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).

Author information

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

Authors
  1. Hong Ji
  2. Lauren I. R. Ehrlich
  3. Jun Seita
  4. Peter Murakami
  5. Akiko Doi
  6. Paul Lindau
  7. Hwajin Lee
  8. Martin J. Aryee
  9. Rafael A. Irizarry
  10. Kitai Kim
  11. Derrick J. Rossi
  12. Matthew A. Inlay
  13. Thomas Serwold
  14. Holger Karsunky
  15. Lena Ho
  16. George Q. Daley
  17. Irving L. Weissman
  18. Andrew P. Feinberg

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 toAndrew P. Feinberg.

Ethics declarations

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.Nature467, 338–342 (2010). https://doi.org/10.1038/nature09367

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Editorial Summary

Stem cells with baggage

Induced pluripotent stem (iPS) cells are produced by reprogramming differentiated adult cells using a cocktail of transcription factors. They share many properties that are characteristic of embryonic stem (ES) cells generated by somatic-cell nuclear transfer (SCNT), and of ES cells from naturally fertilized embryos. The three cell types are not identical, however, and an interesting difference has now been discovered: iPS cells retain an 'epigenetic memory' of the donor tissue from which they derive, whereas SCNT-based reprogramming resets the DNA-methylation state of adult cells so it is closer to the ES cell-like state. In a separate study, Jiet al. examine the role of specific DNA methylation marks in the developmental progression of particular cell lineages. They present a genome-wide DNA-methylation analysis of haematopoietic cell populations that reveals remarkable epigenetic plasticity. Changes in DNA methylation emerge as perhaps a principal factor directing cell-fate choices such as commitment to myeloid or lymphoid development.

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