A transcribed enhancer dictates mesendoderm specification in pluripotency

Nat Commun. 2017 Nov 27;8(1):1806. doi: 10.1038/s41467-017-01804-w.

Abstract

Enhancers and long noncoding RNAs (lncRNAs) are key determinants of lineage specification during development. Here, we evaluate remodeling of the enhancer landscape and modulation of the lncRNA transcriptome during mesendoderm specification. We sort mesendodermal progenitors from differentiating embryonic stem cells (ESCs) according to Eomes expression, and find that enhancer usage is coordinated with mesendoderm-specific expression of key lineage-determining transcription factors. Many of these enhancers are associated with the expression of lncRNAs. Examination of ESC-specific enhancers interacting in three-dimensional space with mesendoderm-specifying transcription factor loci identifies MesEndoderm Transcriptional Enhancer Organizing Region (Meteor). Genetic and epigenetic manipulation of the Meteor enhancer reveal its indispensable role during mesendoderm specification and subsequent cardiogenic differentiation via transcription-independent and -dependent mechanisms. Interestingly, Meteor-deleted ESCs are epigenetically redirected towards neuroectodermal lineages. Loci, topologically associating a transcribed enhancer and its cognate protein coding gene, appear to represent therefore a class of genomic elements controlling developmental competence in pluripotency.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / genetics
  • Cell Line
  • Cell Lineage / genetics
  • Ectoderm / cytology
  • Ectoderm / physiology*
  • Embryonic Stem Cells / physiology*
  • Enhancer Elements, Genetic / physiology*
  • Gene Expression Profiling / methods
  • Gene Expression Regulation, Developmental / physiology
  • Humans
  • Induced Pluripotent Stem Cells
  • Mesoderm / cytology
  • Mesoderm / physiology*
  • Mice
  • Neural Plate / cytology
  • Neural Plate / physiology
  • RNA, Long Noncoding / physiology*

Substances

  • RNA, Long Noncoding