C/EBPα creates elite cells for iPSC reprogramming by upregulating Klf4 and increasing the levels of Lsd1 and Brd4

Nat Cell Biol. 2016 Apr;18(4):371-81. doi: 10.1038/ncb3326. Epub 2016 Mar 14.

Abstract

Reprogramming somatic cells into induced pluripotent stem cells (iPSCs) is typically inefficient and has been explained by elite-cell and stochastic models. We recently reported that B cells exposed to a pulse of C/EBPα (Bα' cells) behave as elite cells, in that they can be rapidly and efficiently reprogrammed into iPSCs by the Yamanaka factors OSKM. Here we show that C/EBPα post-transcriptionally increases the abundance of several hundred proteins, including Lsd1, Hdac1, Brd4, Med1 and Cdk9, components of chromatin-modifying complexes present at super-enhancers. Lsd1 was found to be required for B cell gene silencing and Brd4 for the activation of the pluripotency program. C/EBPα also promotes chromatin accessibility in pluripotent cells and upregulates Klf4 by binding to two haematopoietic enhancers. Bα' cells share many properties with granulocyte/macrophage progenitors, naturally occurring elite cells that are obligate targets for leukaemic transformation, whose formation strictly requires C/EBPα.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / metabolism
  • Blotting, Western
  • CCAAT-Enhancer-Binding Protein-alpha / genetics*
  • CCAAT-Enhancer-Binding Protein-alpha / metabolism
  • Cell Line
  • Cells, Cultured
  • Cellular Reprogramming / genetics*
  • Female
  • Gene Expression Profiling / methods
  • Gene Ontology
  • HEK293 Cells
  • Histone Demethylases / genetics*
  • Histone Demethylases / metabolism
  • Humans
  • Induced Pluripotent Stem Cells / metabolism*
  • Kruppel-Like Transcription Factors / genetics*
  • Kruppel-Like Transcription Factors / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mouse Embryonic Stem Cells / metabolism
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Proteomics / methods
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Up-Regulation

Substances

  • Brd4 protein, mouse
  • CCAAT-Enhancer-Binding Protein-alpha
  • GKLF protein
  • Kruppel-Like Transcription Factors
  • Nuclear Proteins
  • Transcription Factors
  • Histone Demethylases
  • KDM1a protein, mouse