2. Academic Validation
  3. A neuronal cell-based reporter system for monitoring the activity of HDAC2

A neuronal cell-based reporter system for monitoring the activity of HDAC2

  • SLAS Discov. 2022 Oct 11;S2472-5552(22)13702-0. doi: 10.1016/j.slasd.2022.10.001.
Kazuhiro Unemura 1,  Masako Kawano 2,  Mai Takakura 2,  Ikuko Iwata 2,  Kana Hyakkoku 3,  Naotaka Horiguchi 3,  Tomohiko Okuda 4,  Yukinori Hirano 5
Affiliations

Affiliations

  • 1 Medical innovation center, SK project, Kyoto University Graduate School of Medicine, Konoecho, Yoshida, Sakyo-ku, Kyoto, Kyoto 606-8315 Japan; Shionogi & Co., Ltd. Laboratory for Drug Discovery and Disease Research, Shionogi Pharmaceutical Research Center, 3-1-1, Futaba-cho, Toyonaka-shi, Osaka, 561-0825, Japan.
  • 2 Medical innovation center, SK project, Kyoto University Graduate School of Medicine, Konoecho, Yoshida, Sakyo-ku, Kyoto, Kyoto 606-8315 Japan.
  • 3 Shionogi & Co., Ltd. Laboratory for Drug Discovery and Disease Research, Shionogi Pharmaceutical Research Center, 3-1-1, Futaba-cho, Toyonaka-shi, Osaka, 561-0825, Japan.
  • 4 Shionogi & Co., Ltd. Laboratory for Bio-Drug Discovery, Shionogi Pharmaceutical Research Center, 3-1-1, Futaba-cho, Toyonaka-shi, Osaka, 561-0825, Japan.
  • 5 Medical innovation center, SK project, Kyoto University Graduate School of Medicine, Konoecho, Yoshida, Sakyo-ku, Kyoto, Kyoto 606-8315 Japan; Division of Life Science, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
PMID: 36240996 DOI: 10.1016/j.slasd.2022.10.001
Abstract

Given that histone acetylation via histone acetyltransferases (HATs) and histone deacetylases (HDACs) is significant in memory formation, HDAC2 has been thoroughly investigated as a potential therapeutic target for the treatment of cognitive dysfunction. Although HDAC inhibitors have been discovered through in vitro Enzyme assay, off-target effects on Other HDACs are common due to their conserved catalytic domains. Each HDAC could be regulated by specific intracellular molecular mechanisms, raising the possibility that a cell-based assay could identify selective inhibitors targeting specific HDACs through their regulatory mechanisms. Here, we propose a versatile, cell-based reporter system for screening HDAC2 inhibitors. Through RNA-sequencing from human cultured neuronal cells, we determined that expression of a transcriptional repressor, inhibitor of DNA binding 1 (ID1), is increased by knockdown of HDAC2. We also established the knock-in neuronal cell lines of a bioluminescence reporter gene to ID1. The knock-in cell lines showed significant reporter activity by known HDAC inhibitors and by HDAC2-knockdown but not by HDAC1-knockdown. Thus, our neuronal cell-based reporter system is a promising method for screening the specific inhibitors of HDAC2 but not HDAC1, by potentially targeting not only HDAC2, but also the regulatory mechanisms of HDAC2 in neurons.

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