Epigenetic inheritance of circadian period in clonal cells

  1. Yan Li
  2. Yongli Shan
  3. Gokhul Krishna Kilaru
  4. Stefano Berto
  5. Guang-Zhong Wang
  6. Kimberly H Cox
  7. Seung-Hee Yoo
  8. Shuzhang Yang
  9. Genevieve Konopka
  10. Joseph S Takahashi  Is a corresponding author
  1. University of Texas Southwestern Medical Center, United States
  2. Shanghai Institutes for Biological Sciences, China
  3. University of Texas Health Science Houston, United States
  4. Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, United States

Abstract

Circadian oscillations are generated via transcriptional-translational negative feedback loops. However, individual cells from fibroblast cell lines have heterogeneous rhythms, oscillating independently and with different period lengths. Here we showed that heterogeneity in circadian period is heritable and used a multi-omics approach to investigate underlying mechanisms. By examining large-scale phenotype-associated gene expression profiles in hundreds of mouse clonal cell lines, we identified and validated multiple novel candidate genes involved in circadian period determination in the absence of significant genomic variants. We also discovered differentially co-expressed gene networks that were functionally associated with period length. We further demonstrated that global differential DNA methylation bidirectionally regulated these same gene networks. Interestingly, we found that depletion of DNMT1 and DNMT3A had opposite effects on circadian period, suggesting non-redundant roles in circadian gene regulation. Together, our findings identify novel gene candidates involved in periodicity, and reveal DNA methylation as an important regulator of circadian periodicity.

Data availability

RNA Sequencing data have been deposited in GEO under accession codes: GSE132663 and GSE132665. Exome sequencing data have been deposited in SRA under accession number: PRJNA548837. All data generated or analyzed during this study are included in the manuscript and supporting files. Source data have been provided for Figures 2 and 4.

The following data sets were generated

Article and author information

Author details

  1. Yan Li

    Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Yongli Shan

    Neuroscience, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Gokhul Krishna Kilaru

    Neuroscience, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Stefano Berto

    Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Guang-Zhong Wang

    Key Laboratory of Computational Biology, Shanghai Institutes for Biological Sciences, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6432-8310
  6. Kimberly H Cox

    Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Seung-Hee Yoo

    Biochemistry, University of Texas Health Science Houston, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Shuzhang Yang

    Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Genevieve Konopka

    Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3363-7302
  10. Joseph S Takahashi

    Department of Neuroscience, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, United States
    For correspondence
    joseph.takahashi@utsouthwestern.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0384-8878

Funding

Howard Hughes Medical Institute

  • Joseph S Takahashi

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

Reviewing Editor

  1. Amita Sehgal, Howard Hughes Medical Institute, University of Pennsylvania, United States

Version history

  1. Received: December 5, 2019
  2. Accepted: May 26, 2020
  3. Accepted Manuscript published: May 27, 2020 (version 1)
  4. Version of Record published: June 11, 2020 (version 2)

Copyright

© 2020, Li 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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  1. Yan Li
  2. Yongli Shan
  3. Gokhul Krishna Kilaru
  4. Stefano Berto
  5. Guang-Zhong Wang
  6. Kimberly H Cox
  7. Seung-Hee Yoo
  8. Shuzhang Yang
  9. Genevieve Konopka
  10. Joseph S Takahashi
(2020)
Epigenetic inheritance of circadian period in clonal cells
eLife 9:e54186.
https://doi.org/10.7554/eLife.54186

Share this article

https://doi.org/10.7554/eLife.54186

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