Methylated cis-regulatory elements mediate KLF4-dependent gene transactivation and cell migration
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 preferentiall...
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eLife Sciences Publications Ltd
2017-05-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/20068 |
| _version_ | 1828166737838735360 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Jun Wan |
| collection | DOAJ |
| description | 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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| id | doaj.art-d716f1aa3cb8430d8b1faa4456209df4 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T02:06:16Z |
| publishDate | 2017-05-01 |
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| spelling | doaj.art-d716f1aa3cb8430d8b1faa4456209df42022-12-22T03:52:31ZengeLife Sciences Publications LtdeLife2050-084X2017-05-01610.7554/eLife.20068Methylated cis-regulatory elements mediate KLF4-dependent gene transactivation and cell migrationJun Wan0Yijing Su1Qifeng Song2Brian Tung3Olutobi Oyinlade4https://orcid.org/0000-0002-8932-2764Sheng Liu5Mingyao Ying6Guo-li Ming7Hongjun Song8Jiang Qian9Heng Zhu10Shuli Xia11https://orcid.org/0000-0001-5849-6967The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, United StatesDepartment of Neurology, Johns Hopkins University School of Medicine, Baltimore, United States; Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, United StatesDepartment 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 StatesDepartment of Neurology, Johns Hopkins University School of Medicine, Baltimore, United States; Hugo W Moser Research Institute at Kennedy Krieger, Baltimore, United StatesDepartment of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, United StatesThe Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, United StatesDepartment of Neurology, Johns Hopkins University School of Medicine, Baltimore, United States; Hugo W Moser Research Institute at Kennedy Krieger, Baltimore, United StatesDepartment of Neurology, Johns Hopkins University School of Medicine, Baltimore, United StatesDepartment of Neurology, Johns Hopkins University School of Medicine, Baltimore, United StatesThe 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 StatesDepartment 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 StatesDepartment of Neurology, Johns Hopkins University School of Medicine, Baltimore, United StatesAltered 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.https://elifesciences.org/articles/20068DNA methylationhistone modificationcell migrationKLF4 |
| spellingShingle | 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 Methylated cis-regulatory elements mediate KLF4-dependent gene transactivation and cell migration eLife DNA methylation histone modification cell migration KLF4 |
| title | Methylated cis-regulatory elements mediate KLF4-dependent gene transactivation and cell migration |
| title_full | Methylated cis-regulatory elements mediate KLF4-dependent gene transactivation and cell migration |
| title_fullStr | Methylated cis-regulatory elements mediate KLF4-dependent gene transactivation and cell migration |
| title_full_unstemmed | Methylated cis-regulatory elements mediate KLF4-dependent gene transactivation and cell migration |
| title_short | Methylated cis-regulatory elements mediate KLF4-dependent gene transactivation and cell migration |
| title_sort | methylated cis regulatory elements mediate klf4 dependent gene transactivation and cell migration |
| topic | DNA methylation histone modification cell migration KLF4 |
| url | https://elifesciences.org/articles/20068 |
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