title: A Synthetic DNA-Binding Domain Guides Distinct Chromatin-Modifying Small Molecules to Activate an Identical Gene Network.
abstract: Synthetic dual-function ligands targeting specific DNA sequences and histone-modifying enzymes were applied to achieve regulatory control over multi-gene networks in living cells. Unlike the broad array of targeting small molecules for histone deacetylases (HDACs), few modulators are known for histone acetyltransferases (HATs), which play a central role in transcriptional control. As a novel chemical approach to induce selective HAT-regulated genes, we conjugated a DNA-binding domain (DBD) "I" to N-(4-chloro-3-trifluoromethyl-phenyl)-2-ethoxy-benzamide (CTB), an artificial HAT activator. In vitro enzyme activity assays and microarray studies were used to demonstrate that distinct functional small molecules could be transformed to have identical bioactivity when conjugated with a targeting DBD. This proof-of-concept synthetic strategy validates the switchable functions of HDACs and HATs in gene regulation and provides a molecular basis for developing versatile bioactive ligands.
authors.affiliation: Department of Chemistry, Graduate School of Science, Kyoto University Kitashirakawa-Oiwakecho, Sakyo-ku, Kyoto 606-8502 (Japan).|Shanghai Key Laboratory of Chemical Biology, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology, Meilong Road 130, Shanghai, 200237 (China).
authors.forename: Le
authors.initials: L
authors.lastname: Han
authors.affiliation: Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University Yoshida-Ushinomiyacho, Sakyo-ku, Kyoto 606-8501 (Japan).
authors.forename: Ganesh N
authors.initials: GN
authors.lastname: Pandian
authors.affiliation: Department of Chemistry, Graduate School of Science, Kyoto University Kitashirakawa-Oiwakecho, Sakyo-ku, Kyoto 606-8502 (Japan).
authors.forename: Anandhakumar
authors.initials: A
authors.lastname: Chandran
authors.affiliation: Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University Yoshida-Ushinomiyacho, Sakyo-ku, Kyoto 606-8501 (Japan).
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Sato
authors.affiliation: Department of Chemistry, Graduate School of Science, Kyoto University Kitashirakawa-Oiwakecho, Sakyo-ku, Kyoto 606-8502 (Japan).
authors.forename: Junichi
authors.initials: J
authors.lastname: Taniguchi
authors.affiliation: Department of Chemistry, Graduate School of Science, Kyoto University Kitashirakawa-Oiwakecho, Sakyo-ku, Kyoto 606-8502 (Japan).
authors.forename: Gengo
authors.initials: G
authors.lastname: Kashiwazaki
authors.affiliation: Department of Chemistry, Graduate School of Science, Kyoto University Kitashirakawa-Oiwakecho, Sakyo-ku, Kyoto 606-8502 (Japan).
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Sawatani
authors.affiliation: Department of Chemistry, Graduate School of Science, Kyoto University Kitashirakawa-Oiwakecho, Sakyo-ku, Kyoto 606-8502 (Japan).
authors.forename: Kaori
authors.initials: K
authors.lastname: Hashiya
authors.affiliation: Department of Chemistry, Graduate School of Science, Kyoto University Kitashirakawa-Oiwakecho, Sakyo-ku, Kyoto 606-8502 (Japan).
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Bando
authors.affiliation: Shanghai Key Laboratory of Chemical Biology, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology, Meilong Road 130, Shanghai, 200237 (China).
authors.forename: Yufang
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Shanghai Key Laboratory of Chemical Biology, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology, Meilong Road 130, Shanghai, 200237 (China).
authors.forename: Xuhong
authors.initials: X
authors.lastname: Qian
authors.affiliation: Department of Chemistry, Graduate School of Science, Kyoto University Kitashirakawa-Oiwakecho, Sakyo-ku, Kyoto 606-8502 (Japan). hs@kuchem.kyoto-u.ac.jp.|Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University Yoshida-Ushinomiyacho, Sakyo-ku, Kyoto 606-8501 (Japan). hs@kuchem.kyoto-u.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sugiyama
mesh_terms: D001549:Benzamides / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D004247:DNA / Q000235:genetics / Q000378:metabolism*; D044127:Epigenesis, Genetic / Q000187:drug effects; D053263:Gene Regulatory Networks / Q000187:drug effects*; D051548:Histone Acetyltransferases / Q000737:chemistry / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D017434:Protein Structure, Tertiary; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D001549:Benzamides; D006657:Histones; D054852:Small Molecule Libraries; D004247:DNA; D051548:Histone Acetyltransferases
keywords: DNA recognition; epigenetics; gene expression; histone modification; synthetic biology