A delayed h3k27me3 accumulation after DNA replication of embryonic stem cells opens chromatin for lineage specific transcription factors to bind and initiate differentiation

Introduction Pluripotent stem cells (PSCs) have been useful to generate differentiated progenies for cell replacement therapy, and disease models. The Parkinson’s Disease (PD) field was arguably one of the first to have embraced the promise of stem cells. However, regardless of the differentiation protocols used, cultures and grafts continue to contain multiple cell types with midbrain dopamine (mDA) neural progenitors (NPs) and neurons representing only a fraction of total cells in the dish or graft. During cell differentiation, recruitment of transcription factors (TFs) to repressed genes in euchromatin is essential to activate new transcriptional programs, which is impeded by condensed H3K27me3-containing chromatin. Here, using single-cell and gene-specific analyses, we tested the hypothesis that during the first hours of induction of differentiation of human embryonic stem cells (ESCs), accumulation of the repressive histone mark H3K27me3 is delayed after DNA replication, indicative of decondensed chromatin structure, potentially providing a critical ‘window of opportunity’ for recruitment of lineage-specific TFs to DNA. If true, it may be possible to direct the differentiation of ESCs or iPSCs into homogeneous populations of any desired cell type needed to study, model and potentially treat different diseases including PD. Poster presented at: ISSCR 2017 in Boston MA, United States