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Synthetic Small Molecules for Epigenetic Activation of Pluripotency Genes in Mouse Embryonic Fibroblasts

  1. Dr. Ganesh N. Pandian1,†,
  2. Dr. Ken-ichi Shinohara1,2,5,†,
  3. Dr. Akimichi Ohtsuki2,
  4. Yusuke Nakano2,
  5. Dr. Minoshima Masafumi2,
  6. Dr. Toshikazu Bando2,
  7. Prof. Hiroki Nagase3,6,
  8. Prof. Yasuhiro Yamada4,
  9. Dr. Akira Watanabe4,
  10. Prof. Naohiro Terada5,
  11. Shinsuke Sato1,
  12. Hironobu Morinaga2,
  13. Prof. Hiroshi Sugiyama1,2,*

Article first published online: 28 OCT 2011

DOI: 10.1002/cbic.201100597

Issue

ChemBioChem

ChemBioChem

Volume 12, Issue 18, pages 2822–2828, December 16, 2011

Additional Information

How to Cite

Pandian, G. N., Shinohara, K.-i., Ohtsuki, A., Nakano, Y., Masafumi, M., Bando, T., Nagase, H., Yamada, Y., Watanabe, A., Terada, N., Sato, S., Morinaga, H. and Sugiyama, H. (2011), Synthetic Small Molecules for Epigenetic Activation of Pluripotency Genes in Mouse Embryonic Fibroblasts. ChemBioChem, 12: 2822–2828. doi: 10.1002/cbic.201100597

Author Information

  1. 1

    Institute for Integrated Cell–Material Sciences (iCeMS), Kyoto University, Yoshida Ushinomiya-cho, Sakyo, Kyoto 606-8501 (Japan)

  2. 2

    Department of Science, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502 (Japan)

  3. 3

    Division of Cancer Genetics, Chiba Cancer Center Research Institute, 666-2 Nitona-cho, Chuo-ku, Chiba-shi, Chiba 260-8717 (Japan)

  4. 4

    Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507 (Japan)

  5. 5

    Department of Pathology, College of Medicine, University of Florida, Gainesville, FL 32610-0275 (USA)

  6. 6

    Division of Cancer Genetics, Department of Advanced Medical Science, Nihon University School of Medicine, Tokyo 173-8610 (Japan)

  1. †

    These authors contributed equally to this work.

*Institute for Integrated Cell–Material Sciences (iCeMS), Kyoto University, Yoshida Ushinomiya-cho, Sakyo, Kyoto 606-8501 (Japan)

  1. †

    These authors contributed equally to this work.

Publication History

  1. Issue published online: 9 DEC 2011
  2. Article first published online: 28 OCT 2011
  3. Manuscript Received: 22 SEP 2011

Funded by

  • Ministry of Education, Culture, Sports, Science and Technology of Japan

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Keywords:

  • biomimetic synthesis;
  • chromatin remodeling;
  • DNA recognition;
  • genetic switches;
  • pluripotency genes

Abstract

Considering the essential role of chromatin remodeling in gene regulation, their directed modulation is of increasing importance. To achieve gene activation by epigenetic modification, we synthesized a series of pyrrole–imidazole polyamide conjugates (PIPs) that can bind to predetermined DNA sequences, and attached them with suberoylanilide hydroxamic acid (SAHA), a potent histone deacetylase inhibitor. As histone modification is associated with pluripotency, these new types of conjugates, termed SAHA–PIPs, were screened for their effect on the expression of induced pluripotent stem cell (iPSC) factors. We found certain SAHA–PIPs that could differentially up-regulate the endogenous expression of Oct-3/4, Nanog, Sox2, Klf4 and c-Myc. SAHA and other SAHA–PIPs did not show such induction; this implies a role for PIPs and their sequence specificity in this differential gene activation. Chromatin immunoprecipitation analysis suggested that SAHA–PIP-mediated gene induction proceeds by histone H3 Lys9 and Lys14 acetylation and Lys4 trimethylation, which are epigenetic features associated with transcriptionally active chromatin.

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