Pioneer Transcription factors in programming and reprogramming
Abdenour Soufi is a Chancellor’s fellow at the MRC Centre for Regenerative Medicine and the Institute for Stem Cell Research at the University of Edinburgh. He has obtained a PhD degree in Biophysics from the University of Bristol. Abdenour did his postdoctoral studies with Prof Kenneth Zareth at the University of Pennsylvania, U.S.A. where he performed seminal work on the transcriptional control of reprogramming tissue cells to become stem cells (iPS). He was the first to propose that transcription factors act as pioneer factors during iPS reprogramming (Soufi et al., 2012 Cell, Soufi et al., 2015 Cell). His research is focused on revealing how chromatin structure controls cellular identity. Abdenour has recently received an MRC career development award to engineer synthetic factors that are more potent in cellular reprogramming.
It is astounding to discover that it takes so few transcription factors (TFs) to convert cells from one type to another. Strikingly, the four TFs: Oct4, Sox2, Klf4, and c-Myc (OSKM) are able to convert fibroblasts to become induced pluripotent stem cells (iPSCs), which are highly similar to embryonic stem cells (ESCs). However this reprogramming process is highly inefficient and often results in partially reprogrammed cells. To understand how OSKM initially target silent pluripotency genes, we previously mapped the interaction of OSKM with the somatic genome early in reprogramming. We found that O, S, and K, but not Myc, engage closed chromatin at distal sites, a hallmark of pioneer activity. We have also investigated the differential interaction of O, S, K, and M with nucleosomes, both in vitro and in vivo, revealing that the pioneer activity of reprogramming factors relates to the basic ability of TFs to adapt their DNA-binding domains (DBDs) to target partial motifs exposed on the surface of nucleosomes. Other DBDs that lack such adaptability can bind with pioneer factors to recognize degenerate motifs on nucleosomes. Together our data provide the molecular basis by which pioneer factors interact with nucleosomes to engage silent chromatin, endowing competence for subsequent gene activation.
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