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Dot1l interacts with Zc3h10 to activate Ucp1 and other thermogenic genes

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Cite this article as: eLife 2020;9:e59990 doi: 10.7554/eLife.59990

Abstract

Brown adipose tissue is a metabolically beneficial organ capable of dissipating chemical energy into heat, thereby increasing energy expenditure. Here, we identify Dot1l, the only known H3K79 methyltransferase, as an interacting partner of Zc3h10 that transcriptionally activates the Ucp1 promoter and other BAT genes. Through a direct interaction, Dot1l is recruited by Zc3h10 to the promoter regions of thermogenic genes to function as a coactivator by methylating H3K79. We also show that Dot1l is induced during brown fat cell differentiation and by cold exposure and that Dot1l and its H3K79 methyltransferase activity is required for thermogenic gene program. Furthermore, we demonstrate that Dot1l ablation in mice using Ucp1-Cre prevents activation of Ucp1 and other target genes to reduce thermogenic capacity and energy expenditure, promoting adiposity. Hence, Dot1l plays a critical role in the thermogenic program and may present as a future target for obesity therapeutics.

Data availability

We have deposited ATAC-seq and RNA-seq files in the NCBI database (GSE159645)

The following data sets were generated

Article and author information

Author details

  1. Danielle Yi

    Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Hai P Nguyen

    Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Jennie Dinh

    Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Jose A Viscarra

    Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Ying Xie

    Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Frances Lin

    Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Madeleine Zhu

    Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Jon M Dempersmier

    Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Yuhui Wang

    Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Hei Sook Sul

    Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, United States
    For correspondence
    hsul@berkeley.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3372-5097

Funding

NIH Office of the Director (DK120075)

  • Hei Sook Sul

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

Reviewing Editor

  1. Peter Tontonoz, University of California, Los Angeles, United States

Publication history

  1. Received: June 13, 2020
  2. Accepted: October 26, 2020
  3. Accepted Manuscript published: October 27, 2020 (version 1)
  4. Version of Record published: November 12, 2020 (version 2)

Copyright

© 2020, Yi 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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