Genome-Wide Definition of Promoter and Enhancer Usage during Neural Induction of Human Embryonic Stem Cells

PLoS One. 2015 May 15;10(5):e0126590. doi: 10.1371/journal.pone.0126590. eCollection 2015.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Differentiation / genetics
  • Cell Line
  • Chromosome Mapping / methods
  • Enhancer Elements, Genetic / genetics*
  • Epigenesis, Genetic / genetics
  • Genome, Human / genetics
  • Genome-Wide Association Study / methods
  • Histones / genetics
  • Human Embryonic Stem Cells / cytology*
  • Humans
  • Neurons / cytology
  • Pluripotent Stem Cells / cytology
  • Promoter Regions, Genetic / physiology*
  • RNA, Untranslated / genetics
  • Transcription Initiation Site / physiology
  • Transcription, Genetic / genetics
  • Up-Regulation / genetics


  • Histones
  • RNA, Untranslated

Grant support

This work was supported by grants from the European Research Council (FM; ERC-2010-AdG, GT-SKIN; URL:;), and the Italian Ministry of Education, University and Research (MIUR) FIRB project (AM; RBFR10OS4G; URL: The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.