論文 - 詳細
| 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 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | News |
| 各媒体での言及数の合計 | 14 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | 201B7(HPS0063) |