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Abstract

Transposable element (TE)-derived sequences comprise half of the human genome and DNA methylome and are presumed to be densely methylated and inactive. Examination of genome-wide DNA methylation status within 928 TE subfamilies in human embryonic and adult tissues identified unexpected tissue-specific and subfamily-specific hypomethylation signatures. Genes proximal to tissue-specific hypomethylated TE sequences were enriched for functions important for the relevant tissue type, and their expression correlated strongly with hypomethylation within the TEs. When hypomethylated, these TE sequences gained tissue-specific enhancer marks, including monomethylation of histone H3 at lysine 4 (H3K4me1) and occupancy by p300, and a majority exhibited enhancer activity in reporter gene assays. Many such TEs also harbored binding sites for transcription factors that are important for tissue-specific functions and showed evidence of evolutionary selection. These data suggest that sequences derived from TEs may be responsible for wiring tissue type–specific regulatory networks and may have acquired tissue-specific epigenetic regulation.

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Acknowledgements

We thank the many collaborators at the Reference Epigenome Mapping Centers (REMCs), the Epigenome Data Analysis and Coordination Center and the NCBI who have generated and processed data that were used in this project. We acknowledge the dedicated system administrators at the Washington University Center for Genome Sciences and Systems Biology who have provided an excellent computing environment. We thank the UCSC Genome Browser bioinformatics team for providing processed ENCODE data. We acknowledge support from the US National Institutes of Health (NIH) Roadmap Epigenomics Program, sponsored by the National Institute on Drug Abuse (NIDA) and the National Institute of Environmental Health Sciences (NIEHS). J.F.C., T.W., P.J.F. and M.H. are supported by US NIH grant 5U01ES017154. B.Z. and X.Z. are supported by the NIDA R25 program DA027995. K.L.L. and C.L.M. are supported by US NIH grants P01CA095616 and P01CA142536. T.W. is supported in part by the March of Dimes Foundation, the Edward Mallinckrodt Jr. Foundation, US NIH grant P50CA134254 and a generous start-up package from the Department of Genetics at the Washington University School of Medicine.

Author information

Author notes

    • Mingchao Xie
    • , Chibo Hong
    •  & Bo Zhang

    These authors contributed equally to this work.

Affiliations

  1. Department of Genetics, Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Mingchao Xie
    • , Bo Zhang
    • , Rebecca F Lowdon
    • , Xiaoyun Xing
    • , Daofeng Li
    • , Xin Zhou
    • , Hyung Joo Lee
    •  & Ting Wang
  2. Brain Tumor Research Center, Department of Neurosurgery, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA.

    • Chibo Hong
    •  & Joseph F Costello
  3. Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Cecile L Maire
    •  & Keith L Ligon
  4. Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA.

    • Keith L Ligon
  5. Department of Pathology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA.

    • Philippe Gascard
    • , Mahvash Sigaroudinia
    •  & Thea D Tlsty
  6. Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, California, USA.

    • Theresa Kadlecek
    •  & Arthur Weiss
  7. Division of Rheumatology, University of California, San Francisco, San Francisco, California, USA.

    • Arthur Weiss
  8. Genome Center, University of California–Davis, Davis, California, USA.

    • Henriette O'Geen
  9. Department of Biochemistry & Molecular Biology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA.

    • Peggy J Farnham
  10. Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Pamela A F Madden
  11. BC Cancer Agency, Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia, Canada.

    • Andrew J Mungall
    • , Angela Tam
    • , Baljit Kamoh
    • , Stephanie Cho
    • , Richard Moore
    • , Martin Hirst
    •  & Marco A Marra
  12. Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada.

    • Martin Hirst

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Contributions

J.F.C. and T.W. designed the study. C.L.M., K.L.L., P.G., M.S., T.D.T., T.K. and A.W. collected samples. C.H., H.O., P.J.F., A.J.M., A.T., B.K., S.C., R.M., M.H. and M.A.M. performed sequencing assays. M.X., B.Z., R.F.L., D.L., X.Z., H.J.L., P.A.F.M. and T.W. performed data analysis. C.H., X.X. and M.X. performed bisulfite validation and reporter gene assays. M.X., J.F.C. and T.W. wrote the manuscript. All authors discussed the results and contributed to writing the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Joseph F Costello or Ting Wang.

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DOI

https://doi.org/10.1038/ng.2649

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