Activation of Lineage Regulators and Transposable Elements across a Pluripotent Spectrum

Stem Cell Reports. 2017 Jun 6;8(6):1645-1658. doi: 10.1016/j.stemcr.2017.05.014.

Abstract

Embryonic stem cells (ESCs) are characterized by the pluripotent capacity to generate all embryonic lineages. Here, we show that ESCs can occupy a spectrum of distinct transcriptional and epigenetic states in response to varied extrinsic conditions. This spectrum broadly corresponds to a developmental continuum of pluripotency and is coupled with a gradient of increasing global DNA methylation. Each pluripotent state is linked with activation of distinct classes of transposable elements (TEs), which in turn influence ESCs through generating chimeric transcripts. Moreover, varied ESC culture parameters differentially license heterogeneous activation of master lineage regulators, including Sox1, Gata4, or Blimp1, and influence differentiation. Activation of Blimp1 is prevalent in 2i (without LIF) conditions, and marks a dynamic primordial germ cell (PGC)-like sub-state that is directly repressed by Klf4 downstream of LIF/STAT3 signaling. Thus, extrinsic cues establish a spectrum of pluripotent states, in part by modulating sub-populations, as well as directing the transcriptome, epigenome, and TE.

Keywords: DNA methylation; KLF4; PGC; STAT3; chimeric transcripts; embryonic stem cell; heterogeneity; imprints; pluripotency; transposable element.

MeSH terms

  • Animals
  • CRISPR-Cas Systems / genetics
  • Cell Differentiation
  • Cell Line
  • Cell Lineage
  • DNA Methylation
  • DNA Transposable Elements / genetics*
  • GATA4 Transcription Factor / metabolism
  • Kruppel-Like Factor 4
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / metabolism
  • Leukemia Inhibitory Factor / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mouse Embryonic Stem Cells / cytology
  • Mouse Embryonic Stem Cells / metabolism
  • Pluripotent Stem Cells / cytology
  • Pluripotent Stem Cells / metabolism*
  • Positive Regulatory Domain I-Binding Factor 1 / metabolism
  • Principal Component Analysis
  • SOXB1 Transcription Factors / metabolism
  • STAT3 Transcription Factor / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism

Substances

  • DNA Transposable Elements
  • GATA4 Transcription Factor
  • Gata4 protein, mouse
  • Klf4 protein, mouse
  • Kruppel-Like Factor 4
  • Kruppel-Like Transcription Factors
  • Leukemia Inhibitory Factor
  • Prdm1 protein, mouse
  • SOXB1 Transcription Factors
  • STAT3 Transcription Factor
  • Sox1 protein, mouse
  • Stat3 protein, mouse
  • Transcription Factors
  • Positive Regulatory Domain I-Binding Factor 1