Activation of Lineage Regulators and Transposable Elements across a Pluripotent Spectrum

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. [Display omitted] •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 In this article Surani and colleagues report a spectrum of pluripotent ESC states and characterize the distinct epigenomes and transcriptomes. They find each pluripotent condition is linked with specific transposable elements, influences differentiation, and supports distinct ESC sub-populations. They further trace the signaling principle which regulates one sub-population (a PGC-like state) to show it is modulated by KLF4 downstream of LIF/STAT3.