2. Academic Validation
  3. Small molecules capable of activating DNA methylation-repressed genes targeted by the p38 mitogen-activated protein kinase pathway

Small molecules capable of activating DNA methylation-repressed genes targeted by the p38 mitogen-activated protein kinase pathway

  • J Biol Chem. 2018 May 11;293(19):7423-7436. doi: 10.1074/jbc.RA117.000757.
Xiang Li 1,  Erchang Shang 2,  Qiang Dong 3,  Yingfeng Li 4,  Jing Zhang 5,  Shaohua Xu 6,  Zuodong Zhao 3,  Wei Shao 6,  Cong Lv 7,  Yong Zheng 8,  Hailin Wang 7,  Xiaoguang Lei 2,  Bing Zhu 9,  Zhuqiang Zhang 10
Affiliations

Affiliations

  • 1 Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China; National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; National Institute of Biological Sciences, Beijing 102206, China.
  • 2 Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of the Ministry of Education, Department of Chemical Biology, College of Chemistry and Molecular Engineering, Synthetic and Functional Biomolecules Center, and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
  • 3 National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; National Institute of Biological Sciences, Beijing 102206, China.
  • 4 National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; National Institute of Biological Sciences, Beijing 102206, China; College of Life Sciences, Beijing Normal University, Beijing 100875, China.
  • 5 National Institute of Biological Sciences, Beijing 102206, China; Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of the Ministry of Education, Department of Chemical Biology, College of Chemistry and Molecular Engineering, Synthetic and Functional Biomolecules Center, and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
  • 6 National Institute of Biological Sciences, Beijing 102206, China.
  • 7 State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.
  • 8 National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
  • 9 Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China; National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: zhubing@ibp.ac.cn.
  • 10 National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China. Electronic address: zhangzhuqiang@ibp.ac.cn.
PMID: 29559556 DOI: 10.1074/jbc.RA117.000757
Abstract

Regulation of gene expression by epigenetic modifications such as DNA methylation is crucial for developmental and disease processes, including cell differentiation and Cancer development. Genes repressed by DNA methylation can be derepressed by various compounds that target DNA methyltransferases, histone deacetylases, and other regulatory factors. However, some additional, unknown mechanisms that promote DNA methylation-mediated gene silencing may exist. Chemical agents that can counteract the effects of epigenetic repression that is not regulated by DNA methyltransferases or histone deacetylases therefore may be of research interest. Here, we report the results of a high-throughput screen using a 308,251-member chemical library to identify potent small molecules that derepress an EGFP reporter gene silenced by DNA methylation. Seven hit compounds were identified that did not directly target bulk DNA methylation or histone acetylation. Analyzing the effect of these compounds on endogenous gene expression, we discovered that three of these compounds (compounds LX-3, LX-4, and LX-5) selectively activate the p38 mitogen-activated protein kinase (MAPK) pathway and derepress a subset of endogenous genes repressed by DNA methylation. Selective agonists of the p38 pathway have been lacking, and our study now provides critical compounds for studying this pathway and p38 MAPK-targeted genes repressed by DNA methylation.

Keywords

DNA methylation; gene activation; gene regulation; high-throughput screening (HTS); mitogen-activated protein kinase (MAPK); p38.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-125980
    p38/MAPK抑制剂
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