Activation of Lineage Regulators and Transposable Elements across a Pluripotent Spectrum.
Activation of Lineage Regulators and Transposable Elements across a Pluripotent Spectrum.
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DOI：
10.1016/j.stemcr.2017.05.014
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发表时间：
2017-06-06
影响因子：
5.9
通讯作者：
Surani MA
中科院分区：
文献类型：
--
作者：
Hackett JA;Kobayashi T;Dietmann S;Surani MA
胚胎干细胞(ESCs)的特点是具有多能生成所有胚胎血统的能力。在这里，我们表明，ESCs可以占据一系列不同的转录和表观遗传状态，以响应不同的外部条件。这一光谱广泛地对应于多潜能的发育连续体，并与全球DNA甲基化增加的梯度相结合。每一种多能状态都与不同类别的转座元件(TES)的激活有关，TES通过产生嵌合转录本来影响ESCs。此外，不同的ESC培养参数对包括Sox1、Gata4或Blimp1在内的主要谱系调节因子的异质性激活具有不同的许可作用，并影响分化。Blimp1的激活在2I(不存在LIF)条件下普遍存在，并标志着一种动态的原始生殖细胞(PGC)样亚状态，该亚状态直接被LIF/STAT3信号下游的KLF4抑制。因此，外部线索建立了多能状态的光谱，部分是通过调节亚群，以及指导转录组、表观基因组和TE。不同的培养参数建立了ESC的多能性谱，ESC条件影响DNA甲基化和对分化信号的反应，包括受LIF和KLF4调控的PGC样状态。在本文中，苏拉尼和他的同事报道了一系列多能性ESC状态，并描述了不同的表观基因组和转录本。他们发现，每种多能性状态都与特定的转座元件相关联，影响分化，并支持不同的ESC亚群。他们进一步追踪了调节一个亚群(PGC样状态)的信号原理，以表明它是由LIF/STAT3下游的KLF4调制的。
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. 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.