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

Jun Wan, Yijing Su, Qifeng Song, Brian Tung, Olutobi Oyinlade, Sheng Liu, Mingyao Ying, Guo Li Ming, Hongjun Song, Jiang Qian, Heng Zhu, Shuli Xia

Research output: Research - peer-reviewArticle

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.

LanguageEnglish (US)
Article numbere20068
JournaleLife
Volume6
DOIs
StatePublished - May 29 2017

Fingerprint

Transcriptional Activation
Cell Movement
Genes
GKLF protein
DNA Methylation
Chromatin Assembly and Disassembly
Chromatin
Chemical activation
Regulator Genes
Glioblastoma
Cell Adhesion
Transcription Factors
Mutation
Neoplasms
Cell adhesion
Transcription
Gene expression

ASJC Scopus subject areas

  • Neuroscience(all)
  • Medicine(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Methylated cis-regulatory elements mediate KLF4-dependent gene transactivation and cell migration. / Wan, Jun; Su, Yijing; Song, Qifeng; Tung, Brian; Oyinlade, Olutobi; Liu, Sheng; Ying, Mingyao; Ming, Guo Li; Song, Hongjun; Qian, Jiang; Zhu, Heng; Xia, Shuli.

In: eLife, Vol. 6, e20068, 29.05.2017.

Research output: Research - peer-reviewArticle

Wan J, Su Y, Song Q, Tung B, Oyinlade O, Liu S et al. Methylated cis-regulatory elements mediate KLF4-dependent gene transactivation and cell migration. eLife. 2017 May 29;6. e20068. Available from, DOI: 10.7554/eLife.20068
Wan, Jun ; Su, Yijing ; Song, Qifeng ; Tung, Brian ; Oyinlade, Olutobi ; Liu, Sheng ; Ying, Mingyao ; Ming, Guo Li ; Song, Hongjun ; Qian, Jiang ; Zhu, Heng ; Xia, Shuli. / Methylated cis-regulatory elements mediate KLF4-dependent gene transactivation and cell migration. In: eLife. 2017 ; Vol. 6.
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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.",
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AU - Su,Yijing

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AU - Tung,Brian

AU - Oyinlade,Olutobi

AU - Liu,Sheng

AU - Ying,Mingyao

AU - Ming,Guo Li

AU - Song,Hongjun

AU - Qian,Jiang

AU - Zhu,Heng

AU - Xia,Shuli

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