Radical acceleration of nuclear reprogramming by chromatin remodeling with the transactivation domain of MyoD

Hiroyuki Hirai, Tetsuya Tani, Nobuko Katoku-Kikyo, Steven Kellner, Peter Karian, Meri Firpo, Nobuaki Kikyo*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

63 Scopus citations

Abstract

Induced pluripotent stem cells (iPSCs) can be created by reprogramming differentiated cells through introduction of defined genes, most commonly Oct4, Sox2, Klf4, and c-Myc (OSKM). However, this process is slow and extremely inefficient. Here, we demonstrate radical acceleration of iPSC creation with a fusion gene between Oct4 and the powerful transactivation domain (TAD) of MyoD (M 3O). Transduction of M 3O as well as Sox2, Klf4, and c-Myc into fibroblasts effectively remodeled patterns of DNA methylation, chromatin accessibility, histone modifications, and protein binding at pluripotency genes, raising the efficiency of making mouse and human iPSCs more than 50-fold in comparison to OSKM. These results identified that one of the most critical barriers to iPSC creation is poor chromatin accessibility and protein recruitment to pluripotency genes. The MyoD TAD has a capability of over-coming this problem. Our approach of fusing TADs to unrelated transcription factors has far-reaching implications as a powerful tool for transcriptional reprogramming beyond application to iPSC technology.

Original languageEnglish (US)
Pages (from-to)1349-1361
Number of pages13
JournalStem Cells
Volume29
Issue number9
DOIs
StatePublished - Sep 2011

Keywords

  • Embryonic stem cells
  • Induced pluripotent stem cells
  • MyoD
  • Oct4

ASJC Scopus subject areas

  • Molecular Medicine
  • Developmental Biology
  • Cell Biology

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