TY - JOUR
T1 - Activation of Lineage Regulators and Transposable Elements across a Pluripotent Spectrum
AU - Hackett, Jamie A.
AU - Kobayashi, Toshihiro
AU - Dietmann, Sabine
AU - Surani, M. Azim
N1 - Publisher Copyright:
© 2017 The Author(s)
PY - 2017/6/6
Y1 - 2017/6/6
N2 - 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.
AB - 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.
KW - DNA methylation
KW - KLF4
KW - PGC
KW - STAT3
KW - chimeric transcripts
KW - embryonic stem cell
KW - heterogeneity
KW - imprints
KW - pluripotency
KW - transposable element
UR - http://www.scopus.com/inward/record.url?scp=85020316073&partnerID=8YFLogxK
U2 - 10.1016/j.stemcr.2017.05.014
DO - 10.1016/j.stemcr.2017.05.014
M3 - Article
C2 - 28591649
AN - SCOPUS:85020316073
SN - 2213-6711
VL - 8
SP - 1645
EP - 1658
JO - Stem Cell Reports
JF - Stem Cell Reports
IS - 6
ER -