Esrrb is a pivotal target of the Gsk3/Tcf3 axis regulating embryonic stem cell self-renewal.
Esrrb is a pivotal target of the Gsk3/Tcf3 axis regulating embryonic stem cell self-renewal.
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DOI：
10.1016/j.stem.2012.06.008
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发表时间：
2012-10-05
期刊：
影响因子：
23.9
通讯作者：
Smith, Austin
中科院分区：
文献类型：
--
作者：
Martello, Graziano;Sugimoto, Toshimi;Diamanti, Evangelia;Joshi, Anagha;Hannah, Rebecca;Ohtsuka, Satoshi;Goettgens, Berthold;Niwa, Hitoshi;Smith, Austin
抑制糖原合成酶激酶3 （Gsk3）通过调节Tcf3支持小鼠胚胎干细胞（ESCs），但Tcf3下游的关键靶点尚不清楚。我们分析了基因组定位和转录组数据集之间的交集，以确定Tcf3抑制的基因。其中，Esrrb的操作在功能分析中给出了独特的表型。敲除和敲除消除了对Gsk3抑制的反应，导致多能性标记的消失和集落形成能力的丧失。相反，强迫表达通过抑制分化和维持自我更新来表现Gsk3抑制或Tcf3缺失。因此，核受体Esrrb是介导Gsk3抑制下游自我更新的必要和充分条件。白血病抑制因子（LIF）通过Stat3调控ESCs，独立于Gsk3抑制。与平行操作一致，LIF中的ESCs可容纳Esrrb缺失并保持多能性。这些发现强调了Esrrb在调节初始多能状态中的关键作用，并说明了核心多能因子之间的补偿。►Esrrb是多能性网络中Tcf3抑制的主要靶点►Esrrb对Gsk3抑制下游的自我更新至关重要►Esrrb有效地抑制分化并维持ESC自我更新►Esrrb是一个核心的多能性因子，但可以通过LIF/Stat3进行补偿。抑制糖原合成酶激酶3使胚胎干细胞处于naïve基态。令人惊讶的是，这种作用主要是通过上调单一转录因子Esrrb的表达来介导的。然而，Esrrb功能可以通过Stat3的独立激活来补偿，这证明了支撑多能性的核心网络的可塑性。
Inhibition of glycogen synthase kinase-3 (Gsk3) supports mouse embryonic stem cells (ESCs) by modulating Tcf3, but the critical targets downstream of Tcf3 are unclear. We analyzed the intersection between genome localization and transcriptome data sets to identify genes repressed by Tcf3. Among these, manipulations of Esrrb gave distinctive phenotypes in functional assays. Knockdown and knockout eliminated response to Gsk3 inhibition, causing extinction of pluripotency markers and loss of colony forming capability. Conversely, forced expression phenocopied Gsk3 inhibition or Tcf3 deletion by suppressing differentiation and sustaining self-renewal. Thus the nuclear receptor Esrrb is necessary and sufficient to mediate self-renewal downstream of Gsk3 inhibition. Leukaemia inhibitory factor (LIF) regulates ESCs through Stat3, independently of Gsk3 inhibition. Consistent with parallel operation, ESCs in LIF accommodated Esrrb deletion and remained pluripotent. These findings highlight a key role for Esrrb in regulating the naive pluripotent state and illustrate compensation among the core pluripotency factors. ► Esrrb is the principal target of Tcf3 repression in the pluripotency network ► Esrrb is essential for self-renewal downstream of Gsk3 inhibition ► Esrrb potently suppresses differentiation and sustains ESC self-renewal ► Esrrb is a core pluripotency factor but can be compensated by LIF/Stat3 Inhibition of glycogen synthase kinase 3 keeps embryonic stem cells in a naïve ground state. Surprisingly this effect is mediated mainly by upregulating expression of a single transcription factor Esrrb. Esrrb function can be compensated by independent activation of Stat3, however, demonstrating the plasticity of the core network underpinning pluripotency.
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