Structure-based discovery of NANOG variant with enhanced properties to promote self-renewal and reprogramming of pluripotent stem cells
Abstract
Maintenance and reprogramming of pluripotency are among the most important issues in stem cell biology and regenerative medicine. Pluripotency is governed by several key transcription factors regulating transcription of other factors. Among these, regulation of OCT4 transcription by NANOG (from Irish myth-ology Tír na nÓg) is a critical interaction. We present here the crystal structure of human NANOG homeodomain in complex with the OCT4 promoter DNA and, through a series of ration-ally designed mutations, we identify key functional residues in the protein-DNA interaction, protein stability, and maintenance of mouse ESC self-renewal. Furthermore, we describe a mutation, NANOG L122A, which enhances DNA binding affinity, protein stability, mouse ESC self-renewal, and reprogramming into ground state from primed state pluripotency.
- Publication:
-
Proceedings of the National Academy of Science
- Pub Date:
- April 2015
- DOI:
- 10.1073/pnas.1502855112
- Bibcode:
- 2015PNAS..112.4666H