Reprogramming Factor Expression Initiates Widespread Targeted Chromatin Remodeling

SummaryDespite rapid progress in characterizing transcription factor-driven reprogramming of somatic cells to an induced pluripotent stem cell (iPSC) state, many mechanistic questions still remain. To gain insight into the earliest events in the reprogramming process, we systematically analyzed the transcriptional and epigenetic changes that occur during early factor induction after discrete numbers of divisions. We observed rapid, genome-wide changes in the euchromatic histone modification, H3K4me2, at more than a thousand loci including large subsets of pluripotency-related or developmentally regulated gene promoters and enhancers. In contrast, patterns of the repressive H3K27me3 modification remained largely unchanged except for focused depletion specifically at positions where H3K4 methylation is gained. These chromatin regulatory events precede transcriptional changes within the corresponding loci. Our data provide evidence for an early, organized, and population-wide epigenetic response to ectopic reprogramming factors that clarify the temporal order through which somatic identity is reset during reprogramming.

► Ectopic Oct4, Sox2, Klf4, and c-Myc induce H3K4 methylation at developmental promoters
► Promoter H3K4 methylation precedes transcriptional activation
► Localized depletion of H3K27me3 occurs within CpG island promoters that gain H3K4me2
► H3K4me2 enhancer signatures are gained and lost in response to OSKM factor induction