Primate-specific endogenous retrovirus-driven transcription defines naive-like stem cells
Primate-specific endogenous retrovirus-driven transcription defines naive-like stem cells
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DOI：
10.1038/nature13804
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发表时间：
2014-12-18
期刊：
影响因子：
64.8
通讯作者：
Izsvak, Zsuzsanna
中科院分区：
文献类型：
--
作者：
Wang, Jichang;Xie, Gangcai;Izsvak, Zsuzsanna
由于幼稚胚胎干细胞具有广泛而强大的发育潜力，因此在研究和治疗方面具有很大的前景。虽然这些细胞很容易从小鼠囊胚中获得，但不可能轻易地分离出人类的等量细胞（1,2），尽管通过改变培养条件（2-4）或通过转基因修饰(5)，通过强制使用人类胚胎干细胞来人工生成（而不是提取）人类幼稚样细胞。在这里，我们展示了人类胚胎干细胞（hESCs）和诱导多能干细胞（hiPSCs）培养中的一个亚群表现出幼稚状态细胞的关键特性。这些幼稚样细胞可以被遗传标记，并与HERVH（一种灵长类特异性内源性逆转录病毒）的转录升高有关。HERVH元件为幼稚多能转录因子（包括LBP9）的组合提供功能结合位点，LBP9最近被认为与幼稚疾病有关(6)。LBP9-HERVH驱动hesc特异性替代转录本和嵌合转录本，包括多能性调节的长链非编码rna。LBP9、HERVH和HERVH衍生转录本的破坏会损害自我更新。这些观察结果将HERVH表达定义为幼稚样hESCs的标志，并建立了新的灵长类特异性转录回路调节多能性。
Naive embryonic stem cells hold great promise for research and therapeutics as they have broad and robust developmental potential. While such cells are readily derived from mouse blastocysts it has not been possible to isolate human equivalents easily(1,2), although human naive-like cells have been artificially generated (rather than extracted) by coercion of human primed embryonic stem cells by modifying culture conditions(2-4) or through transgenic modification(5). Here we show that a sub-population within cultures of human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) manifests key properties of naive state cells. These naive-like cells can be genetically tagged, and are associated with elevated transcription of HERVH, a primate-specific endogenous retrovirus. HERVH elements provide functional binding sites for a combination of naive pluripotency transcription factors, including LBP9, recently recognized as relevant to naivety inmice(6). LBP9-HERVH drives hESC-specific alternative and chimaeric transcripts, including pluripotency-modulating long non-coding RNAs. Disruption of LBP9, HERVH and HERVH-derived transcripts compromises self-renewal. These observations define HERVH expression as a hallmark of naive-like hESCs, and establish novel primate-specific transcriptional circuitry regulating pluripotency.