Abstract
Genome-wide mapping of transcriptional regulatory elements is an essential tool for understanding the molecular events orchestrating self-renewal, commitment and differentiation of stem cells. We combined high-throughput identification of transcription start sites with genome-wide profiling of histones modifications to map active promoters and enhancers in embryonic stem cells (ESCs) induced to neuroepithelial-like stem cells (NESCs). Our analysis showed that most promoters are active in both cell types while approximately half of the enhancers are cell-specific and account for most of the epigenetic changes occurring during neural induction, and most likely for the modulation of the promoters to generate cell-specific gene expression programs. Interestingly, the majority of the promoters activated or up-regulated during neural induction have a “bivalent” histone modification signature in ESCs, suggesting that developmentally-regulated promoters are already poised for transcription in ESCs, which are apparently pre-committed to neuroectodermal differentiation. Overall, our study provides a collection of differentially used enhancers, promoters, transcription starts sites, protein-coding and non-coding RNAs in human ESCs and ESC-derived NESCs, and a broad, genome-wide description of promoter and enhancer usage and of gene expression programs characterizing the transition from a pluripotent to a neural-restricted cell fate.
Highlights
Human embryonic stem cells (ESCs) are pluripotent, blastocyst-derived cells endowed with the potential to give rise to all three embryonic germ layer’s derivatives
neuroepithelial-like stem cells (NESCs) stained positive for the neural stem cells markers NES, predominantly expressed in stem cells of the central nervous system [35], in combination with SOX2, a pluripotency transcription factor essential for neural stem cell proliferation and maintenance [36] (Fig 1B)
ESCs and NESCs showed two very distinct transcript phenotypes, with ESCs expressing the pluripotency master regulators OCT4, NANOG and SOX2, and NESCs characterized by the absence of OCT4 and NANOG and the expression of SOX2 together with the marker of neural commitment SOX1, PAX6 and NESTIN
Summary
Human embryonic stem cells (ESCs) are pluripotent, blastocyst-derived cells endowed with the potential to give rise to all three embryonic germ layer’s derivatives. Several protocols have been developed to obtain neural stem cells from ESCs, attempting to recapitulate in vitro the intermediate stages of neural induction, a process marked by the down-regulation of the pluripotency markers OCT4 and NANOG and up-regulation of neuroectodermal-specific markers. Transcriptional Regulation during Neural Induction of Human ESCs in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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