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

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  • Bruno Di Stefano
  • Samuel Collombet
  • Janus Schou Jakobsen
  • Michael Wierer
  • Jose Luis Sardina
  • Andreas Lackner
  • Ralph Stadhouders
  • Carolina Segura-Morales
  • Mirko Francesconi
  • Francesco Limone
  • Matthias Mann
  • Bo Porse
  • Denis Thieffry
  • Thomas Graf
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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.

OriginalsprogEngelsk
TidsskriftNature Cell Biology
Vol/bind18
Udgave nummer4
Sider (fra-til)371-81
ISSN1465-7392
DOI
StatusUdgivet - 14 mar. 2016

ID: 46323637