Gene Regulation, Stems Cells and Cancer


Hematopoietic Stem Cells, Transdifferentiation and Reprogramming

Thomas Graf (ICREA Research Professor)
 Chris van Oevelen
 Jose Luis Sardina (CRG), Tian Tian (BLUEPRINT), Bruno Di Stefano (ERC Synergy), Ralph Stadhouders (EMBO)
 Luisa de Andres (CRG), Alessandro Dasti (Severo Ochoa), Andreas Lackner (Plan Nacional)
 Clara Berenguer (Plan Nacional), Laura Batlle (CRG, GRSC Programme), Carolina Segura (ERC Synergy)  


Fig. 1. Cultures of pre-B cells from reprogrammable mice…


The laboratory is mainly interested in the mechanisms by which transcription factors induced cell fate conversions. Here, we investigate how C/EBPα induces transdifferentiation of B cells into macrophages, a process that can be achieved within 2 to 3 days and at nearly 100% efficiency. We have recently also discovered that a pulse of C/EBPα can poise B cells to rapid and highly efficient reprogramming into induced pluripotent stem (iPS) cells. Because of its speed and efficiency this is an ideal system to study the mechanism of somatic cell reprogramming.

Research Projects

  • What are the epigenetic changes occurring during C/EBPα induced the transdifferentiation of pre-B cells into macrophages and what is their role in the process?
  • How does C/EBPα induce the accessibility of B cell chromatin to pluripotency transcription factors?
  • How does the 3D genome structure change during reprogramming and transdifferentiation, and are they a cause or a consequence of altered gene expression?
  • What is the function of the RNA binding protein Musashi 2 in establishing and maintaining the self-renewal and differentiatioin of hematopietic stem cells?

Selected Publications

Di Stefano, B and Graf, T.
“Time-resolved gene expression profiling during reprogramming of C/EBPα-pulsed B cells into iPS cells.”
Scientific Data, 1. doi:10.1038/sdata (2014).

Di Stefano, B and Graf, T.
“Very Rapid and Efficient Generation of Induced Pluripotent Stem Cells from Mouse pre-B Cells.”
Methods in Molecular Biology, doi:10.1007/7651 (2014).

Di Stefano B, Sardina JL, van Oevelen C, Collombet S, Kallin EM, Vicent GP, Lu J, Thieffry D, Beato M and Graf T.
“C/EBPα poises B cells for rapid reprogramming into iPS cells.”
Nature, 506:235-241 (2014).

Aloia L, Di Stefano B, Sessa A, Morey L, Santanach S, Cozzuto L, Aznar-Benitah S, Graf T, Broccoli V, Di Croce L.
“Zrf1 is required to establish and maintain neural progenitor identity.”
Genes and Development, 28:182-197 (2014).

Rodriguez-Ubreva J, Ciudad L, van Oevelen C, Parra M, Graf T, Ballestar E.
“C/EBPα-Mediated Activation of miR-34a and miR-223 Inhibits Lef1 Expression to Achieve Efficient Reprogramming into Macrophages.”
Mol Cell Biol, 34:1145-1157 (2014).