德国欧洲分子生物学实验室Edith Heard研究小组近日取得一项新成果。他们发现SPEN 调控了X染色体失活（XCI）的转录和表观遗传机制。2020年2月5日，国际学术期刊《自然》在线发表了这一成果。
研究人员发现在小鼠中转录抑制因子SPEN是体内XCI的关键协调器，并阐明了其作用机理。研究人员发现SPEN对于着床前小鼠胚胎和胚胎干细胞中X染色体基因沉默起始至关重要的作用。SPEN对于维持神经祖细胞中XCI也是必不可少的，尽管它显著降低了逃避XCI基因的表达。SPEN在Xist的上调后立即被募集到X染色体，并靶向活性基因的增强子和启动子区。基因沉默后，SPEN会迅速从染色质上脱离，这表明SPEN在染色质上的结合是需要主动转录的。研究人员认为SPOC结构域是SPEN基因沉默的主要效应物，并证明SPOC与Xist RNA的结合足以介导基因沉默。研究人员鉴定了SPOC的蛋白质伴侣，包括NCoR / SMRT、m6A RNA甲基化机制、NuRD复合物、RNA聚合酶II和参与转录起始和延伸调控的因子。研究人员猜想SPEN充当XCI起始的分子整合剂，在活性增强子和启动子区域，将Xist RNA与转录调控以及核小体重塑和组蛋白去乙酰化酶连接起来。
据悉，Xist是长非编码RNA在表观遗传调控中发挥功能的经典范例，尽管其在很大程度上仍无法解释X染色体失活的机制。最近发现了几种与Xist RNA结合的蛋白质，包括转录阻抑因子SPEN，其丢失与多个位点的XCI缺陷有关。
附：英文原文
Title: SPEN integrates transcriptional and epigenetic control of X-inactivation
Author: Franois Dossin, Ins Pinheiro, Jan J. ylicz, Julia Roensch, Samuel Collombet, Agns Le Saux, Tomasz Chelmicki, Mikal Attia, Varun Kapoor, Ye Zhan, Florent Dingli, Damarys Loew, Thomas Mercher, Job Dekker, Edith Heard
Issue&Volume: 2020-02-05
Abstract: Xist represents a paradigm for the function of long non-coding RNA in epigenetic regulation, although how it mediates X-chromosome inactivation (XCI) remains largely unexplained. Several proteins that bind to Xist RNA have recently been identified, including the transcriptional repressor SPEN1,2,3, the loss of which has been associated with deficient XCI at multiple loci2,3,4,5,6. Here we show in mice that SPEN is a key orchestrator of XCI in vivo and we elucidate its mechanism of action. We show that SPEN is essential for initiating gene silencing on the X chromosome in preimplantation mouse embryos and in embryonic stem cells. SPEN is dispensable for maintenance of XCI in neural progenitors, although it significantly decreases the expression of genes that escape XCI. We show that SPEN is immediately recruited to the X chromosome upon the upregulation of Xist, and is targeted to enhancers and promoters of active genes. SPEN rapidly disengages from chromatin upon gene silencing, suggesting that active transcription is required to tether SPEN to chromatin. We define the SPOC domain as a major effector of the gene-silencing function of SPEN, and show that tethering SPOC to Xist RNA is sufficient to mediate gene silencing. We identify the protein partners of SPOC, including NCoR/SMRT, the m6A RNA methylation machinery, the NuRD complex, RNA polymerase II and factors involved in the regulation of transcription initiation and elongation. We propose that SPEN acts as a molecular integrator for the initiation of XCI, bridging Xist RNA with the transcription machinery—as well as with nucleosome remodellers and histone deacetylases—at active enhancers and promoters.
DOI: 10.1038/s41586-020-1974-9
Source: https://www.nature.com/articles/s41586-020-1974-9
Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html
本期文章：《自然》：Online/在线发表
