Counteracting activities of OCT4 and KLF4 during reprogramming to pluripotency

Stem Cell Reports. 2014 Feb 20;2(3):351-65. doi: 10.1016/j.stemcr.2014.01.005. eCollection 2014 Mar 11.

Abstract

Differentiated cells can be reprogrammed into induced pluripotent stem cells (iPSCs) after overexpressing four transcription factors, of which Oct4 is essential. To elucidate the role of Oct4 during reprogramming, we investigated the immediate transcriptional response to inducible Oct4 overexpression in various somatic murine cell types using microarray analysis. By downregulating somatic-specific genes, Oct4 induction influenced each transcriptional program in a unique manner. A significant upregulation of pluripotent markers could not be detected. Therefore, OCT4 facilitates reprogramming by interfering with the somatic transcriptional network rather than by directly initiating a pluripotent gene-expression program. Finally, Oct4 overexpression upregulated the gene Mgarp in all the analyzed cell types. Strikingly, Mgarp expression decreases during the first steps of reprogramming due to a KLF4-dependent inhibition. At later stages, OCT4 counteracts the repressive activity of KLF4, thereby enhancing Mgarp expression. We show that this temporal expression pattern is crucial for the efficient generation of iPSCs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Binding Sites
  • Bone Marrow Cells / cytology
  • Bone Marrow Cells / metabolism
  • Cell Transdifferentiation
  • Cellular Reprogramming*
  • Cluster Analysis
  • Embryonic Stem Cells / cytology
  • Embryonic Stem Cells / metabolism
  • Eye Proteins / genetics
  • Eye Proteins / metabolism
  • Fibroblasts / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental
  • Induced Pluripotent Stem Cells*
  • Kruppel-Like Transcription Factors / chemistry
  • Kruppel-Like Transcription Factors / classification
  • Kruppel-Like Transcription Factors / metabolism*
  • Mice
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism
  • Neural Stem Cells / cytology
  • Neural Stem Cells / metabolism
  • Nucleotide Motifs
  • Octamer Transcription Factor-3 / chemistry
  • Octamer Transcription Factor-3 / classification
  • Octamer Transcription Factor-3 / metabolism*
  • Organ Specificity
  • Protein Binding
  • Transcriptome

Substances

  • Eye Proteins
  • GKLF protein
  • Kruppel-Like Transcription Factors
  • MGARP protein, mouse
  • Mitochondrial Proteins
  • Octamer Transcription Factor-3