Transient and permanent reconfiguration of chromatin and transcription factor occupancy drive reprogramming

Somatic cell reprogramming into pluripotent stem cells (iPSC) through the forced expression of defined factors induces changes in genome architecture reflective of the embryonic stem cell state. However, only a small minority of cells typically transition to pluripotency, which has limited our understanding of what defines cells that successfully reprogram. Here, we characterize the changes that occur across the DNA regulatory landscape during reprogramming by time-course profiling of isolated sub-populations of reprogramming intermediates poised to become iPSC. Widespread reconfiguration of chromatin states and transcription factor occupancy occurs early during reprogramming, and cells that fail to reprogram partially retain regulatory elements active in their somatic cell state. A second wave of reconfiguration occurs just prior to cells achieving pluripotency, where a majority of early changes revert to the somatic cell state and many of the changes that define the pluripotent state become established. Our comprehensive characterization of the molecular changes that occur during reprogramming broaden our understanding of the reprogramming process by providing crucial insights into iPSC generation, and shed light on how transcription factors in general access and change the chromatin during cell fate transitions.