A synthetic DNA-binding inhibitor of SOX2 guides human induced pluripotent stem cells to differentiate into mesoderm
| Autor: | Ganesh N. Pandian, Takuya Hidaka, Junichi Taniguchi, Kaori Hashiya, Hiroshi Sugiyama, Toshikazu Bando, Kyeong Kyu Kim |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
prognosis in palliative care study Mesoderm second heart sound Induced Pluripotent Stem Cells cardiac myocyte Gene Expression Embryoid body dna Biology Cell Line pluripotent 03 medical and health sciences 0302 clinical medicine Directed differentiation SOX2 Chemical Biology and Nucleic Acid Chemistry stem cells Consensus Sequence Genetics medicine Humans Myocytes Cardiac Pyrroles genes preschool imitation and praxis scale Induced pluripotent stem cell genome Wnt Signaling Pathway Induced stem cells Binding Sites Base Sequence SOXB1 Transcription Factors Wnt signaling pathway Cell Differentiation s2 Cell biology Nylons 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Stem cell |
| Zdroj: | Nucleic Acids Research |
| ISSN: | 1362-4962 0305-1048 |
| Popis: | 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. 遺伝子を直接制御する合成分子で組織再生の道が開ける. 京都大学プレスリリース. 2017-09-28. |
| Databáze: | OpenAIRE |
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