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.