文献类型：期刊文献

英文题名：A Synthetic DNA-Binding Domain Guides Distinct Chromatin-Modifying Small Molecules to Activate an Identical Gene Network

作者：Han, Le[1,2];Pandian, Ganesh N.[3];Chandran, Anandhakumar[1];Sato, Shinsuke[3];Taniguchi, Junichi[1];Kashiwazaki, Gengo[1];Sawatani, Yoshito[1];Hashiya, Kaori[1];Bando, Toshikazu[1];Xu, Yufang[2];Qian, Xuhong[2];Sugiyama, Hiroshi[1,3]

机构：[1]Kyoto Univ Kitashirakawa Oiwakecho, Grad Sch Sci, Dept Chem, Sakyo Ku, Kyoto 6068502, Japan;[2]E China Univ Sci & Technol, Shanghai Key Lab Chem Biol, Sch Pharm, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China;[3]Kyoto Univ Yoshida Ushinomiyacho, Inst Integrated Cell Mat Sci WPI iCeMS, Sakyo Ku, Kyoto 6068501, Japan

年份：2015

卷号：54

期号：30

起止页码：8700

外文期刊名：ANGEWANDTE CHEMIE-INTERNATIONAL EDITION

收录：;EI(收录号：20152500959657);WOS:【SCI-EXPANDED(收录号:WOS:000358051600020)】；

基金：This work was supported by JSPS KAKENHI (24225005), "Basic Science and Platform Technology Program for Innovative Biological Medicine" and "JSPS-NSF International Collaborations in Chemistry (ICC)" to H.S. and Grant No. 24310155 to T.B. We also thank challenging exploratory research grant for support to G.N.P. China Scholarship Council (CSC) support L.H.

语种：英文

外文关键词：DNA recognition; epigenetics; gene expression; histone modification; synthetic biology

摘要：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. Invitro 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.