Abstract

Gains and losses in DNA methylation are prominent features of mammalian cell types. To gain insight into the mechanisms that promote shifts in DNA methylation and contribute to changes in cell fate, including malignant transformation, we performed genome-wide mapping of 5-methylcytosine and 5-hydroxymethylcytosine in purified mouse hematopoietic stem cells. We discovered extended regions of low methylation (canyons) that span conserved domains frequently containing transcription factors and are distinct from CpG islands and shores. About half of the genes in these methylation canyons are coated with repressive histone marks, whereas the remainder are covered by activating histone marks and are highly expressed in hematopoietic stem cells (HSCs). Canyon borders are demarked by 5-hydroxymethylcytosine and become eroded in the absence of DNA methyltransferase 3a (Dnmt3a). Genes dysregulated in human leukemias are enriched for canyon-associated genes. The new epigenetic landscape we describe may provide a mechanism for the regulation of hematopoiesis and may contribute to leukemia development.

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Acknowledgements

We thank T. Chen, J.P. Issa, J. Gilbert and members of the Goodell laboratory for helpful discussions. This work was supported by US National Institutes of Health (NIH) grants AG036562, CA126752, DK092883, CA125123, DK084259 and AI07495, the Ellison Medical Foundation, Cancer Prevention Research Institute of Texas (CPRIT) grant RP110028 and the Samuel Waxman Foundation (M.A.G.): by CPRIT RP110471, NIH grant RO1HG007538 and DOD PC094421 (W.L.); and by grants CA151535 and CIRM RM1-01729 and Leukemia and Lymphoma Society award 6187-12 (A.R.). Y.H. and M.K. are supported by Leukemia and Lymphoma Society fellowships.

Author information

Author notes

    • Grant A Challen

    Present address: Department of Internal Medicine, Washington University at St. Louis, St. Louis, Missouri, USA.

    • Mira Jeong
    • , Deqiang Sun
    •  & Min Luo

    These authors contributed equally to this work.

    • Wei Li
    •  & Margaret A Goodell

    These authors jointly directed this work.

Affiliations

  1. Stem Cells and Regenerative Medicine Center, Department of Pediatrics and Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, USA.

    • Mira Jeong
    • , Min Luo
    • , Grant A Challen
    • , Xiaotian Zhang
    • , Liubin Yang
    •  & Margaret A Goodell
  2. Division of Biostatistics, Dan L. Duncan Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.

    • Deqiang Sun
    • , Benjamin Rodriguez
    •  & Wei Li
  3. Division of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.

    • Yun Huang
    • , Lukas Chavez
    • , Myunggon Ko
    •  & Anjana Rao
  4. Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.

    • Hui Wang
    •  & Rui Chen
  5. Department of Hematology, Cambridge Institute for Medical Research and Wellcome Trust and Medical Research Council Cambridge Stem Cell Institute, Cambridge University, Cambridge, UK.

    • Rebecca Hannah
    •  & Berthold Göttgens
  6. Department of Systems Biology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

    • Sang-Bae Kim
    •  & Ju-Seog Lee
  7. Department of Pathology, Baylor College of Medicine, Houston, Texas, USA.

    • Preethi Gunaratne
  8. Department of Biology & Biochemistry, University of Houston, Houston, Texas, USA.

    • Preethi Gunaratne
  9. Department of Medicine, University of Chicago, Chicago, Illinois, USA.

    • Lucy A Godley
  10. Huffington Center for Aging, Baylor College of Medicine, Houston, Texas, USA.

    • Gretchen J Darlington

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Contributions

M.J., M.L., G.A.C., X.Z., Y.H., M.K., H.W., L.Y. and R.C. designed and performed experiments. M.J., D.S., M.L., G.A.C., B.R., L.C., S.-B.K., R.H., L.A.G., A.R., G.J.D., W.L. and M.A.G. analyzed data. M.J., D.S., M.L., G.A.C., B.R., J.-S.L., B.G., P.G., L.A.G., G.J.D., A.R., W.L. and M.A.G. wrote and edited the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Wei Li or Margaret A Goodell.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–12

Excel files

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    Supplementary Table 1

    Whole-genome sequencing statistics

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    Supplementary Table 2

    UMRs in WT HSCs

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    Supplementary Table 3

    UMRs in HOX genes

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    Supplementary Table 4

    UMRs in ESCs

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    Supplementary Table 5

    Canyons versus UMRs

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    Supplementary Table 6

    WT versus Dnmt3a KO HSC UMRs

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    Supplementary Table 7

    5hmC sites in WT and Dnmt3a KO

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    Supplementary Table 8

    oxBS sequencing

  9. 9.

    Supplementary Table 9

    Summary of genes overlapping leukemia Oncomine signatures

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DOI

https://doi.org/10.1038/ng.2836

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