Reprogramming of somatic cells into induced pluripotent stem (iPS) cells can be achieved through the forced expression of defined transcription factors. This induction of pluripotency requires global change in the organisation of chromatin accessibility, transcription factor occupancy and epigenetic states that is highly similar to that of embryonic stem cells. However, the reprogramming process is inefficient, with only a minority of cells completing the full transition to pluripotency, which has been a limiting factor in studying the epigenomic changes that occur during reprogramming.

To further understand the changes that occur across the DNA regulatory landscape during cellular reprogramming of mouse fibroblasts, we isolated sub-populations of reprogramming intermediates that were poised to become iPSCs and performed time-course genome-wide profiling of reprogramming of transcription factor binding (ChIP-seq), chromatin accessibility (ATAC-seq), gene expression (RNA-seq) and DNA methylation (MethylC-seq) throughout the whole reprogramming process. Our results show that induction of reprogramming factors initiates an early wave of widespread chromatin reconfiguration coupled with transient gene expression change and transcription factor binding. A second wave of reconfiguration occurs just prior to cells making the final transition to the pluripotent state, where a majority of early wave chromatin states are reverted and the majority of iPSC factor binding sites and chromatin states become established. The first wave of change is coincident with gradual change in DNA methylation, with the second wave of reconfiguration being coupled with widespread reduction in DNA methylation as the cells acquire pluripotency.

This integrative temporal analysis of provides a comprehensive view of the changes that occur across the DNA regulatory landscape during reprogramming of somatic cells to iPS cells.