Fgf and Esrrb integrate epigenetic and transcriptional networks that regulate self-renewal of trophoblast stem cells.
Fgf and Esrrb integrate epigenetic and transcriptional networks that regulate self-renewal of trophoblast stem cells.
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DOI：
10.1038/ncomms8776
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发表时间：
2015-07-24
影响因子：
16.6
通讯作者：
Hemberger M
中科院分区：
文献类型：
--
作者：
Latos PA;Goncalves A;Oxley D;Mohammed H;Turro E;Hemberger M
Esrrb（雌激素相关受体β）是与胚胎干（ES）细胞自我更新有关的转录因子，但其敲除由于滋养层发育缺陷而导致子宫内致死。在这里，我们表明，在滋养层干（TS）细胞，Esrrb是成纤维细胞生长因子（Fgf）信号转导的下游目标，是至关重要的驱动TS细胞自我更新。与其在ES细胞中多能性相关基因座的占据相反，Esrrb通过直接结合和调节TS细胞特异性转录因子（包括Elf 5和Eomes）来维持TS细胞的干细胞性。为了阐明Esrrb控制其靶点表达的机制，我们使用质谱法表征了其TS细胞特异性相互作用组。与ES细胞不同，Esrrb在TS细胞中与组蛋白去甲基化酶Lsd 1和RNA聚合酶II相关的整合剂复合物相互作用。我们的研究结果提供了新的见解一般和上下文依赖性布线的转录因子网络在干细胞中的主转录因子。 转录因子雌激素相关受体β，Esrrb，调节胚胎干细胞中的多能性基因，但它如何在滋养层干细胞（TS）中起作用尚不清楚。在这里，作者将Esrrb确定为Fgf/Mek信号传导的主要靶点，并概述了一种独特的TS细胞特异性相互作用组以维持干性。
Esrrb (oestrogen-related receptor beta) is a transcription factor implicated in embryonic stem (ES) cell self-renewal, yet its knockout causes intrauterine lethality due to defects in trophoblast development. Here we show that in trophoblast stem (TS) cells, Esrrb is a downstream target of fibroblast growth factor (Fgf) signalling and is critical to drive TS cell self-renewal. In contrast to its occupancy of pluripotency-associated loci in ES cells, Esrrb sustains the stemness of TS cells by direct binding and regulation of TS cell-specific transcription factors including Elf5 and Eomes. To elucidate the mechanisms whereby Esrrb controls the expression of its targets, we characterized its TS cell-specific interactome using mass spectrometry. Unlike in ES cells, Esrrb interacts in TS cells with the histone demethylase Lsd1 and with the RNA Polymerase II-associated Integrator complex. Our findings provide new insights into both the general and context-dependent wiring of transcription factor networks in stem cells by master transcription factors. The transcription factor estrogen-related receptor beta, Esrrb, regulates pluripotency genes in embryonic stem cells, but how it acts in trophoblast stem (TS) cells is unclear. Here, the authors identify Esrrb as a primary target of Fgf/Mek signaling and outline a unique TS cell-specific interactome to sustain stemness.