Activation of Lineage Regulators and Transposable Elements across a Pluripotent Spectrum

Hackett JA et al. (2017) Stem Cell Reports DOI: 10.1016/j.stemcr.2017.05.014

Highlights from the paper

• Diverse culture parameters establish a spectrum of ESC pluripotency
• Activation of distinct transposable elements in each pluripotent state
• ESC conditions influence DNA methylation and response to differentiation cues
• Distinct heterogeneities including a PGC-like state regulated by LIF and KLF4

Summary from the paper

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.

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