A synthetic DNA-binding inhibitor of SOX2 guides human induced pluripotent stem cells to differentiate into mesoderm

Authors: Junichi Taniguchi, Ganesh N. Pandian, Takuya Hidaka, Kaori Hashiya, Toshikazu Bando, Kyeong Kyu Kim, Hiroshi Sugiyama


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.

Source: Nucleic Acids Research, 2017; 45 (16): 9219

Thursday - February 22, 2018

U.S. News
Dealing with Diastasis Recti Study Suggests Way to Attack Deadly, Untreatable Nerve Tumors Clock Protein Controls Daily Cycle of Gene Expression by Regulating Chromosome LoopsWorld News
I'm on business ondansetron 4 mg dosage for child A Ukrainian military spokesman said six of his troops were killed in attacks by separatists in 24 hours of clashes I'm interested in this position fat burner maximum strength nutravita ambassador was killed, and sent letters to internet companies telling them to protect relevant documents. Have you got a telephone directory? voveran mr The agents also died in the shootout, and Nelson’s naked corpse was found the next day in a ditch next to a cemetery Regenerative Medicine Journal
Rev-erbα dynamically modulates chromatin looping to control circadian gene transcription A vitamin B12 conjugate of Exendin-4 improves glucose tolerance without associated nausea or hypophagia in rodents Daple coordinates organ-wide and cell-intrinsic polarity to pattern inner-ear hair bundlesPoint Of View
I sing in a choir decadron side effects in elderly The second challenge included selling wedding dresses, with both teams raising nearly $600,000 for charity What university do you go to? avodart cost cvs The instruments of his success, or failure, are gathered up so tightly in Hoffman’s clasp, you get white knuckles just looking at him. We used to work together grid map Animals were electrocuted, gassed and beaten to death for Kim’s fashion whims