Synthetic small molecules for epigenetic activation of pluripotency genes in mouse embryonic fibroblasts.

Research paper by Ganesh N GN Pandian, Ken-ichi K Shinohara, Akimichi A Ohtsuki, Yusuke Y Nakano, Minoshima M Masafumi, Toshikazu T Bando, Hiroki H Nagase, Yasuhiro Y Yamada, Akira A Watanabe, Naohiro N Terada, Shinsuke S Sato, Hironobu H Morinaga, Hiroshi H Sugiyama

Indexed on: 01 Nov '11Published on: 01 Nov '11Published in: ChemBioChem


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.