Methylated cis-regulatory elements mediate KLF4-denpendent gene transactivation and cell migration

  1. Jun Wan
  2. Yijing Su
  3. Qifeng Song
  4. Brian Tung
  5. Olutobi Oyinlade
  6. Sheng Liu
  7. Mingyao Ying
  8. Guo-li Ming
  9. Hongjun Song
  10. Jiang Qian  Is a corresponding author
  11. Heng Zhu  Is a corresponding author
  12. Shuli Xia  Is a corresponding author
  1. Indiana University School of Medicine, United States
  2. Johns Hopkins University School of Medicine, United States

Abstract

Altered DNA methylation status is associated with human diseases and cancer; however, the underlying molecular mechanisms remain elusive. We previously identified many human transcription factors, including Krüppel-like factor 4 (KLF4), as sequence-specific DNA methylation readers that preferentially recognize methylated CpG (mCpG), here we report the biological function of mCpG-dependent gene regulation by KLF4 in glioblastoma cells. We show that KLF4 promotes cell adhesion, migration, and morphological changes, all of which are abolished by R458A mutation. Surprisingly, 116 genes are directly activated via mCpG-dependent KLF4 binding activity. In-depth mechanistic studies reveal that recruitment of KLF4 to the methylated cis-regulatory elements of these genes result in chromatin remodeling and transcription activation. Our study demonstrates a new paradigm of DNA methylation-mediated gene activation and chromatin remodeling, and provides a general framework to dissect the biological functions of DNA methylation readers and effectors.

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Author details

  1. Jun Wan

    Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Yijing Su

    Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Qifeng Song

    Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Brian Tung

    Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Olutobi Oyinlade

    Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Sheng Liu

    The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Mingyao Ying

    Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Guo-li Ming

    Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Hongjun Song

    Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Jiang Qian

    The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, United States
    For correspondence
    jiang.qian@jhmi.edu
    Competing interests
    The authors declare that no competing interests exist.
  11. Heng Zhu

    Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, United States
    For correspondence
    hzhu4@jhmi.edu
    Competing interests
    The authors declare that no competing interests exist.
  12. Shuli Xia

    Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, United States
    For correspondence
    xia@kennedykrieger.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5849-6967

Funding

National Institutes of Health (R01NS091165)

  • Shuli Xia

National Institutes of Health (EY024580)

  • Jiang Qian

National Institutes of Health (R01 GM111514)

  • Heng Zhu

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

Reviewing Editor

  1. Bing Ren, University of California, San Diego School of Medicine, United States

Publication history

  1. Received: August 20, 2016
  2. Accepted: May 24, 2017
  3. Accepted Manuscript published: May 29, 2017 (version 1)
  4. Version of Record published: June 9, 2017 (version 2)

Copyright

© 2017, Wan 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. Jun Wan
  2. Yijing Su
  3. Qifeng Song
  4. Brian Tung
  5. Olutobi Oyinlade
  6. Sheng Liu
  7. Mingyao Ying
  8. Guo-li Ming
  9. Hongjun Song
  10. Jiang Qian
  11. Heng Zhu
  12. Shuli Xia
(2017)
Methylated cis-regulatory elements mediate KLF4-denpendent gene transactivation and cell migration
eLife 6:e20068.
https://doi.org/10.7554/eLife.20068
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