title: A Multi-target Small Molecule for Targeted Transcriptional Activation of Therapeutically Significant Nervous System Genes.
abstract: An 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.
authors.affiliation: Department of Chemistry Graduate School of Science Kyoto University Kitashirakawa-oiwakecho, Sakyo-ku Kyoto 606-8502 Japan.
authors.forename: Yulei
authors.initials: Y
authors.lastname: Wei
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: Tingting
authors.initials: T
authors.lastname: Zou
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: 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: 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: Thangavel
authors.initials: T
authors.lastname: Vaijayanthi
authors.affiliation: Department of Chemistry Graduate School of Science Kyoto University Kitashirakawa-oiwakecho, Sakyo-ku Kyoto 606-8502 Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Hidaka
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: Department of Chemistry Graduate School of Science Kyoto University Kitashirakawa-oiwakecho, Sakyo-ku Kyoto606-8502 Japan; Institute for Integrated Cell-Material Sciences (WPI-iCeMS) Kyoto University Yoshida-ushinomiyacho, Sakyo-ku Kyoto 606-8501 Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sugiyama
keywords: DNA recognition; brain and nervous system; multi-target small molecules; polymerase chain reaction; synthetic biology