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
Affiliations
Jun Wan
The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, United States
Yijing Su
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, United States; Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, United States
Qifeng Song
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, United States; Center for High-Throughput Biology, Johns Hopkins University School of Medicine, Baltimore, United States
Brian Tung
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, United States; Hugo W Moser Research Institute at Kennedy Krieger, Baltimore, United States
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, United States
Sheng Liu
The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, United States
Mingyao Ying
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, United States; Hugo W Moser Research Institute at Kennedy Krieger, Baltimore, United States
Guo-li Ming
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, United States
Hongjun Song
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, United States
Jiang Qian
The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, United States; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, United States; Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, United States; The Solomon Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States
Heng Zhu
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, United States; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, United States; Center for High-Throughput Biology, Johns Hopkins University School of Medicine, Baltimore, United States; Hugo W Moser Research Institute at Kennedy Krieger, Baltimore, United States
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.
