Abdenour Soufi

University of Edinburgh, The Institute of Stem Cell  Research, Centre for Regenerative Medicine, and the Institute for Regeneration and Repair, UK

Cellular reprogramming to induced pluripotent stem cells (iPSCs) is a powerful technology with  huge  potential  in  regenerative  medicine, disease  modelling,  and  drug  discovery.  However,  reprogramming remains  highly  inefficient  and  often  lacks  specificity,  which  poses challenges for safe applications in clinical settings. One major obstacle of this process is how the transcription factors (TFs) OCT4, SOX2, KLF4 and  MYC  together  known  as  OSKM search  and  find their target  genes.  This  is  especially challenging as genomic DNA highly packaged to fit inside the nucleus. To achieve this packaging, DNA is first wrapped into beads-on-string structures known as nucleosomes, which are further condensed by other proteins to form chromatin fibres and loops. Therefore, TFs must find their target genes in this highly condensed chromatin environment. In this talk, I will present our recent data of how OSKM work together to recognize a precise combination of DNA motifs that are displayed by an array of nucleosomes in distinct 3D arrangements. Surprisingly, we found that this combinatorial motif code is not the destination of OSKM but used as signposts to guide or funnel OSKM binding on chromatin loops until they find their gene targets. In fact, OSKM can be misguided if these motifs were changed, pointing towards the opposite direction. In conclusion, we  propose  a  guided-search  model  by  which TF  combinations  can  navigate  the  chromatin landscape to find their cell-type-specific target genes. This understanding will help us to improve the effectiveness of reprogramming. We can also use this knowledge to understand how diseases such as cancer arise when the wrong genes get activated.