Yulei Wei1, Ganesh N. Pandian2, Tingting Zou1, Junichi Taniguchi1, Shinsuke Sato2, Gengo Kashiwazaki1, Thangavel Vaijayanthi1, T. Hidaka1, Toshikazu Bando1, Hiroshi Sugiyama1,2
1Department of Chemistry, Graduate School of Science, Kyoto University, Kitashirakawa-Oiwakecho, Sakyo-ku, Kyoto 606-8502, Japan
2Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Yoshida-ushinomiyacho, Sakyo-ku, Kyoto 606-8501, Japan
Tóm tắt
AbstractAn integrated multi‐target small molecule capable of altering dynamic epigenetic and transcription programs associated with the brain and nervous system has versatile applications in the regulation of therapeutic and cell‐fate genes. Recently, we have been constructing targeted epigenetic ON switches by integrating sequence‐specific DNA binding pyrrole‐imidazole polyamides with a potent histone deacetylase inhibitor SAHA. Here, we identified a DNA‐based epigenetic ON switch termed SAHA‐L as the first‐ever multi‐target small molecule capable of inducing transcription programs associated with the human neural system and brain synapses networks in BJ human foreskin fibroblasts and 201B7‐iPS cells. Ingenuity pathway analysis showed that SAHA‐L activates the signaling of synaptic receptors like glutamate and γ‐aminobutyric acid, which are key components of autism spectrum disorders. The long‐term incubation of SAHA‐L in 201B7‐iPS cells induced morphology changes and promoted a neural progenitor state. Our finding suggests that the tunable SAHA‐L could be advanced as a cell‐type‐independent multi‐target small molecule for therapeutic and/or cell‐fate gene modulation.
