1. Biochemistry and Chemical Biology
  2. Cell Biology
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OGT binds a conserved C-terminal domain of TET1 to regulate TET1 activity and function in development

  1. Joel Hrit
  2. Leeanne Goodrich
  3. Cheng Li
  4. Bang-An Wang
  5. Ji Nie
  6. Xiaolong Cui
  7. Elizabeth Allene Martin
  8. Eric Simental
  9. Jenna Fernandez
  10. Monica Y Liu
  11. Joseph R Nery
  12. Rosa Castanon
  13. Rahul M Kohli
  14. Natalia Tretyakova
  15. Chuan He
  16. Joseph R Ecker
  17. Mary Goll
  18. Barbara Panning  Is a corresponding author
  1. University of California, San Francisco, United States
  2. Memorial Sloan Kettering Cancer Center, United States
  3. Salk Institute for Biological Studies, United States
  4. University of Chicago, United States
  5. University of Minnesota, United States
  6. University of Pennsylvania, United States
Research Article
  • Cited 18
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Cite this article as: eLife 2018;7:e34870 doi: 10.7554/eLife.34870

Abstract

TET enzymes convert 5-methylcytosine to 5-hydroxymethylcytosine and higher oxidized derivatives. TETs stably associate with and are post-translationally modified by the nutrient-sensing enzyme OGT, suggesting a connection between metabolism and the epigenome. Here, we show for the first time that modification by OGT enhances TET1 activity in vitro. We identify a TET1 domain that is necessary and sufficient for binding to OGT and report a point mutation that disrupts the TET1-OGT interaction. We show that this interaction is necessary for TET1 to rescue hematopoetic stem cell production in tet mutant zebrafish embryos, suggesting that OGT promotes TET1's function during development. Finally, we show that disrupting the TET1-OGT interaction in mouse embryonic stem cells changes the abundance of TET2 and 5-methylcytosine, which is accompanied by alterations in gene expression. These results link metabolism and epigenetic control, which may be relevant to the developmental and disease processes regulated by these two enzymes.

Data availability

5hmC-Seal data has been uploaded to GEO under accession GSE119500.High throughput RNA-seq and WGBS data has been uploaded to GEO under accession GSE119666.

The following data sets were generated

Article and author information

Author details

  1. Joel Hrit

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Leeanne Goodrich

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Cheng Li

    Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Bang-An Wang

    Genomic Analysis Laboratory, Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Ji Nie

    Departments of Chemistry, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Xiaolong Cui

    Departments of Chemistry, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Elizabeth Allene Martin

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Eric Simental

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Jenna Fernandez

    Department of Medicinal Chemistry, University of Minnesota, Minneapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Monica Y Liu

    Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Joseph R Nery

    Genomic Analysis Laboratory, Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Rosa Castanon

    Genomic Analysis Laboratory, Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Rahul M Kohli

    Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Natalia Tretyakova

    Department of Medicinal Chemistry, University of Minnesota, Minneapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Chuan He

    Department of Chemistry, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4319-7424
  16. Joseph R Ecker

    Genomic Analysis Laboratory, Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5799-5895
  17. Mary Goll

    Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  18. Barbara Panning

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    For correspondence
    barbara.panning@gmail.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8301-1172

Funding

National Cancer Institute (P30 CA008748)

  • Cheng Li
  • Mary Goll

California Institute for Regenerative Medicine (TG2-01153)

  • Joel Hrit
  • Barbara Panning

National Institutes of Health (R01 GM088506)

  • Joel Hrit
  • Leeanne Goodrich
  • Barbara Panning

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Daniel Zilberman, John Innes Centre, United Kingdom

Publication history

  1. Received: January 6, 2018
  2. Accepted: October 15, 2018
  3. Accepted Manuscript published: October 16, 2018 (version 1)
  4. Version of Record published: November 2, 2018 (version 2)

Copyright

© 2018, Hrit et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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