Structurally-discovered KLF4 variants accelerate and stabilize reprogramming to pluripotency

Evgeniia Borisova, Ken Nishimura, Yuri An, Miho Takami, Jingyue Li, Dan Song, Mami Matsuo-Takasaki, Dorian Luijkx, Shiho Aizawa, Akihiro Kuno, Eiji Sugihara, Taka aki Sato, Fumiaki Yumoto, Tohru Terada, Koji Hisatake, Yohei Hayashi

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

Abstract

Non-genetically modified somatic cells can only be inefficiently and stochastically reprogrammed to pluripotency by exogenous expression of reprogramming factors. Low competence of natural reprogramming factors may prevent the majority of cells to successfully and synchronously reprogram. Here we screened DNA-interacting amino acid residues in the zinc-finger domain of KLF4 for enhanced reprogramming efficiency using alanine-substitution scanning methods. Identified KLF4 L507A mutant accelerated and stabilized reprogramming to pluripotency in both mouse and human somatic cells. By testing all the variants of L507 position, variants with smaller amino acid residues in the KLF4 L507 position showed higher reprogramming efficiency. L507A bound more to promoters or enhancers of pluripotency genes, such as KLF5, and drove gene expression of these genes during reprogramming. Molecular dynamics simulations predicted that L507A formed additional interactions with DNA. Our study demonstrates how modifications in amino acid residues of DNA-binding domains enable next-generation reprogramming technology with engineered reprogramming factors.

Original languageEnglish
Article number103525
JournaliScience
Volume25
Issue number1
DOIs
Publication statusPublished - 21-01-2022

All Science Journal Classification (ASJC) codes

  • General

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