Residual pluripotency is required for inductive germ cell segregation

• Published in: EMBO reports 2021-08, Vol.22 (8), p.n/a
• Main Authors: Aramaki, Shinya, Kagiwada, Saya, Wu, Guangming, Obridge, David, Adachi, Kenjiro, Kutejova, Eva, Lickert, Heiko, Hübner, Karin, Schöler, Hans R
• Format: Article
• Language: English
• Subjects: Binding; Cell activation; Cell culture; Cell differentiation; Cell fate; cell fate determination; Differentiation (biology); EMBO09; EMBO11; EMBO34; Germ cells; Loci; mesoderm; Oct-4 protein; Pluripotency; Primitive streak; Regulatory mechanisms (biology); T(Brachyury); Transcription factors
• ISSN: 1469-221X; 1469-3178
• DOI: 10.15252/embr.202152553

Fine-tuned dissolution of pluripotency is critical for proper cell differentiation. Here we show that the mesodermal transcription factor, T, globally affects the properties of pluripotency through binding to Oct4 and to the loci of other pluripotency regulators. Strikingly, lower T levels coordinately affect naïve pluripotency, thereby directly activating the germ cell differentiation program, in contrast to the induction of germ cell fate of primed models. Contrary to the effect of lower T levels, higher T levels more severely affect the pluripotency state, concomitantly enhancing the somatic differentiation program and repressing the germ cell differentiation program. Consistent with such in vitro findings, nascent germ cells in vivo are detected in the region of lower T levels at the posterior primitive streak. Furthermore, T and core pluripotency regulators co-localize at the loci of multiple germ cell determinants responsible for germ cell development. In conclusion, our findings indicate that residual pluripotency establishes the earliest and fundamental regulatory mechanism for inductive germline segregation from somatic lineages. SYNOPSIS The mesodermal transcription factor T/Brachyury disrupts defined pluripotency and establishes a specific finely tuned pluripotency state as the earliest regulatory mechanism for inductive germline segregation from somatic lineages. The transcription factor T disrupts defined pluripotency by binding to the loci of Oct4 and other pluripotency regulators. In parallel to the disruption of naïve pluripotency, a specific level of T directly activates germ cell differentiation. The residual pluripotency state generated by a specific level of T is essential for the activation of germ cell determinants. Graphical Abstract The mesodermal transcription factor T/Brachyury disrupts defined pluripotency and establishes a specific finely tuned pluripotency state as the earliest regulatory mechanism for inductive germline segregation from somatic lineages.