RRC ID 52324
著者 Taniguchi J, Pandian GN, Hidaka T, Hashiya K, Bando T, Kim KK, Sugiyama H.
タイトル A synthetic DNA-binding inhibitor of SOX2 guides human induced pluripotent stem cells to differentiate into mesoderm.
ジャーナル Nucleic Acids Res
Abstract Targeted differentiation of human induced pluripotent stem cells (hiPSCs) using only chemicals would have value-added clinical potential in the regeneration of complex cell types including cardiomyocytes. Despite the availability of several chemical inhibitors targeting proteins involved in signaling pathways, no bioactive synthetic DNA-binding inhibitors, targeting key cell fate-controlling genes such as SOX2, are yet available. Here, we demonstrate a novel DNA-based chemical approach to guide the differentiation of hiPSCs using pyrrole-imidazole polyamides (PIPs), which are sequence-selective DNA-binding synthetic molecules. Harnessing knowledge about key transcriptional changes during the induction of cardiomyocyte, we developed a DNA-binding inhibitor termed PIP-S2, targeting the 5'-CTTTGTT-3' and demonstrated that inhibition of SOX2-DNA interaction by PIP-S2 triggers the mesoderm induction in hiPSCs. Genome-wide gene expression analyses revealed that PIP-S2 induced mesoderm by targeted alterations in SOX2-associated gene regulatory networks. Also, employment of PIP-S2 along with a Wnt/β-catenin inhibitor successfully generated spontaneously contracting cardiomyocytes, validating our concept that DNA-binding inhibitors could drive the directed differentiation of hiPSCs. Because PIPs can be fine-tuned to target specific DNA sequences, our DNA-based approach could be expanded to target and regulate key transcription factors specifically associated with desired cell types.
巻・号 45(16)
ページ 9219-9228
公開日 2017-9-19
DOI 10.1093/nar/gkx693
PII 4056716
PMID 28934500
PMC PMC5766170
MeSH Base Sequence Binding Sites Cell Differentiation / drug effects* Cell Line Consensus Sequence Gene Expression Humans Induced Pluripotent Stem Cells / cytology Induced Pluripotent Stem Cells / drug effects* Induced Pluripotent Stem Cells / metabolism Mesoderm / cytology* Mesoderm / drug effects Mesoderm / metabolism Myocytes, Cardiac / cytology* Myocytes, Cardiac / metabolism Nylons / chemistry Nylons / pharmacology* Pyrroles / chemistry Pyrroles / pharmacology* SOXB1 Transcription Factors / antagonists & inhibitors* SOXB1 Transcription Factors / metabolism Wnt Signaling Pathway / drug effects
IF 11.502
引用数 19
リソース情報
ヒト・動物細胞 201B7(HPS0063)