1. Cell Biology
  2. Developmental Biology

Dot1l interacts with Zc3h10 to activate Ucp1 and other thermogenic genes

  1. Danielle Yi
  2. Hai P Nguyen
  3. Jennie Dinh
  4. Jose A Viscarra
  5. Ying Xie
  6. Frances Lin
  7. Madeleine Zhu
  8. Jon M Dempersmier
  9. Yuhui Wang
  10. Hei Sook Sul  Is a corresponding author
  1. University of California, Berkeley, United States
https://doi.org/10.7554/eLife.59990
Share this article
Cite this article
  1. Danielle Yi
  2. Hai P Nguyen
  3. Jennie Dinh
  4. Jose A Viscarra
  5. Ying Xie
  6. Frances Lin
  7. Madeleine Zhu
  8. Jon M Dempersmier
  9. Yuhui Wang
  10. Hei Sook Sul
(2020)
Dot1l interacts with Zc3h10 to activate Ucp1 and other thermogenic genes
eLife 9:e59990.
https://doi.org/10.7554/eLife.59990
  2. Download BibTeX
  3. Download .RIS

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

Version 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.

Metrics

  • 1,292
    views
  • 214
    downloads
  • 10
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Danielle Yi
  2. Hai P Nguyen
  3. Jennie Dinh
  4. Jose A Viscarra
  5. Ying Xie
  6. Frances Lin
  7. Madeleine Zhu
  8. Jon M Dempersmier
  9. Yuhui Wang
  10. Hei Sook Sul
(2020)
Dot1l interacts with Zc3h10 to activate Ucp1 and other thermogenic genes
eLife 9:e59990.
https://doi.org/10.7554/eLife.59990

Share this article

https://doi.org/10.7554/eLife.59990

Categories and tags

Research organism

Further reading

    1. Cell Biology
    2. Computational and Systems Biology

    Multi-omic analysis of bat versus human fibroblasts reveals altered central metabolism

    N Suhas Jagannathan, Javier Yu Peng Koh ... Lisa Tucker-Kellogg
    Research Article

    Bats have unique characteristics compared to other mammals, including increased longevity and higher resistance to cancer and infectious disease. While previous studies have analyzed the metabolic requirements for flight, it is still unclear how bat metabolism supports these unique features, and no study has integrated metabolomics, transcriptomics, and proteomics to characterize bat metabolism. In this work, we performed a multi-omics data analysis using a computational model of metabolic fluxes to identify fundamental differences in central metabolism between primary lung fibroblast cell lines from the black flying fox fruit bat (Pteropus alecto) and human. Bat cells showed higher expression levels of Complex I components of electron transport chain (ETC), but, remarkably, a lower rate of oxygen consumption. Computational modeling interpreted these results as indicating that Complex II activity may be low or reversed, similar to an ischemic state. An ischemic-like state of bats was also supported by decreased levels of central metabolites and increased ratios of succinate to fumarate in bat cells. Ischemic states tend to produce reactive oxygen species (ROS), which would be incompatible with the longevity of bats. However, bat cells had higher antioxidant reservoirs (higher total glutathione and higher ratio of NADPH to NADP) despite higher mitochondrial ROS levels. In addition, bat cells were more resistant to glucose deprivation and had increased resistance to ferroptosis, one of the characteristics of which is oxidative stress. Thus, our studies revealed distinct differences in the ETC regulation and metabolic stress responses between human and bat cells.

    1. Cell Biology
    2. Developmental Biology

    Caenorhabditis elegans SEL-5/AAK1 regulates cell migration and cell outgrowth independently of its kinase activity

    Filip Knop, Apolena Zounarova ... Marie Macůrková
    Research Article

    During Caenorhabditis elegans development, multiple cells migrate long distances or extend processes to reach their final position and/or attain proper shape. The Wnt signalling pathway stands out as one of the major coordinators of cell migration or cell outgrowth along the anterior-posterior body axis. The outcome of Wnt signalling is fine-tuned by various mechanisms including endocytosis. In this study, we show that SEL-5, the C. elegans orthologue of mammalian AP2-associated kinase AAK1, acts together with the retromer complex as a positive regulator of EGL-20/Wnt signalling during the migration of QL neuroblast daughter cells. At the same time, SEL-5 in cooperation with the retromer complex is also required during excretory canal cell outgrowth. Importantly, SEL-5 kinase activity is not required for its role in neuronal migration or excretory cell outgrowth, and neither of these processes is dependent on DPY-23/AP2M1 phosphorylation. We further establish that the Wnt proteins CWN-1 and CWN-2 together with the Frizzled receptor CFZ-2 positively regulate excretory cell outgrowth, while LIN-44/Wnt and LIN-17/Frizzled together generate a stop signal inhibiting its extension.

    1. Biochemistry and Chemical Biology
    2. Cell Biology

    Hsp47 promotes biogenesis of multi-subunit neuroreceptors in the endoplasmic reticulum

    Ya-Juan Wang, Xiao-Jing Di ... Ting-Wei Mu
    Research Article Updated

    Protein homeostasis (proteostasis) deficiency is an important contributing factor to neurological and metabolic diseases. However, how the proteostasis network orchestrates the folding and assembly of multi-subunit membrane proteins is poorly understood. Previous proteomics studies identified Hsp47 (Gene: SERPINH1), a heat shock protein in the endoplasmic reticulum lumen, as the most enriched interacting chaperone for gamma-aminobutyric acid type A (GABAA) receptors. Here, we show that Hsp47 enhances the functional surface expression of GABAA receptors in rat neurons and human HEK293T cells. Furthermore, molecular mechanism study demonstrates that Hsp47 acts after BiP (Gene: HSPA5) and preferentially binds the folded conformation of GABAA receptors without inducing the unfolded protein response in HEK293T cells. Therefore, Hsp47 promotes the subunit-subunit interaction, the receptor assembly process, and the anterograde trafficking of GABAA receptors. Overexpressing Hsp47 is sufficient to correct the surface expression and function of epilepsy-associated GABAA receptor variants in HEK293T cells. Hsp47 also promotes the surface trafficking of other Cys-loop receptors, including nicotinic acetylcholine receptors and serotonin type 3 receptors in HEK293T cells. Therefore, in addition to its known function as a collagen chaperone, this work establishes that Hsp47 plays a critical and general role in the maturation of multi-subunit Cys-loop neuroreceptors.