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.
['Hackett|Jamie A|JA|', 'Kobayashi|Toshihiro|T|', 'Dietmann|Sabine|S|', 'Surani|M Azim|MA|']
D000818:Animals D064113:CRISPR-Cas Systems D002454:Cell Differentiation D002460:Cell Line D019070:Cell Lineage D019175:DNA Methylation D004251:DNA Transposable Elements D050991:GATA4 Transcription Factor D000090062:Kruppel-Like Factor 4 D051741:Kruppel-Like Transcription Factors D053605:Leukemia Inhibitory Factor D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D000066450:Mouse Embryonic Stem Cells D039904:Pluripotent Stem Cells D000074462:Positive Regulatory Domain I-Binding Factor 1 D025341:Principal Component Analysis D055748:SOXB1 Transcription Factors D050796:STAT3 Transcription Factor D014157:Transcription Factors
transposable element pluripotency embryonic stem cell DNA methylation chimeric transcripts heterogeneity KLF4 STAT3 PGC imprints