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

Abstract
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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.

Data availability

The following data sets were generated

1. Wan J
2. Su Y
3. Song Q
4. Tung B
5. Oyinlade O
6. Liu S
7. Ying M
8. Ming G
9. Song H
10. Qian J
11. Zhu H
12. Xia S
(2017) Methylation DNA mediated KLF4 binding activity in glioblastoma cells
Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE97632).

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE97632

Article and author information

Author details

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.
Yijing Su

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, United States

Competing interests
The authors declare that no competing interests exist.
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.
Brian Tung

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, United States

Competing interests
The authors declare that no competing interests exist.
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.
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.
Mingyao Ying

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, United States

Competing interests
The authors declare that no competing interests exist.
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.
Hongjun Song

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, United States

Competing interests
The authors declare that no competing interests exist.
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.
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.
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.

"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.

Copyright

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.