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首页> 外文期刊>PLoS Genetics >Anchoring of Heterochromatin to the Nuclear Lamina Reinforces Dosage Compensation-Mediated Gene Repression
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Anchoring of Heterochromatin to the Nuclear Lamina Reinforces Dosage Compensation-Mediated Gene Repression

机译：异染色质锚定到核层上增强了剂量补偿介导的基因抑制。

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Higher order chromosome structure and nuclear architecture can have profound effects on gene regulation. We analyzed how compartmentalizing the genome by tethering heterochromatic regions to the nuclear lamina affects dosage compensation in the nematode C . elegans . In this organism, the dosage compensation complex (DCC) binds both X chromosomes of hermaphrodites to repress transcription two-fold, thus balancing gene expression between XX hermaphrodites and XO males. X chromosome structure is disrupted by mutations in DCC subunits. Using X chromosome paint fluorescence microscopy, we found that X chromosome structure and subnuclear localization are also disrupted when the mechanisms that anchor heterochromatin to the nuclear lamina are defective. Strikingly, the heterochromatic left end of the X chromosome is less affected than the gene-rich middle region, which lacks heterochromatic anchors. These changes in X chromosome structure and subnuclear localization are accompanied by small, but significant levels of derepression of X-linked genes as measured by RNA-seq, without any observable defects in DCC localization and DCC-mediated changes in histone modifications. We propose a model in which heterochromatic tethers on the left arm of the X cooperate with the DCC to compact and peripherally relocate the X chromosomes, contributing to gene repression. Author Summary DNA isolated from the nucleus of a single human cell, if stretched out, would be 3 meters long. This amount of DNA must be packaged into a nucleus, which is orders of magnitude smaller. DNA of active genes tends to be loosely packed and localized internally within the nucleus, while DNA of inactive genes tends to be tightly packed and localized near the nuclear periphery. We studied the effects of DNA compaction and nuclear localization on gene expression levels using regulation of the X chromosomes in the nematode Caenorhabditis elegans as a model. In this organism, hermaphrodites have two X chromosomes, and males have only one. Genes on the two X chromosomes in hermaphrodites are expressed at half the level compared to the male X, such that the two Xs together express as much gene products as the single X in males. We found that silent regions at the left end of hermaphrodite X chromosomes are tethered to the nuclear periphery, and these tethers are used to build a compact chromosome structure. If this process is defective, gene expression levels are elevated, but less than two-fold. These results indicate that chromosome compaction and nuclear localization contribute to influencing gene expression levels, but other mechanisms must also contribute.
机译：高阶染色体结构和核结构可对基因调控产生深远影响。我们分析了如何通过将异色区域束缚到核层来分隔基因组，从而影响线虫C中的剂量补偿。线虫。在这种生物中，剂量补偿复合物（DCC）结合雌雄同体的两个X染色体，以抑制转录的两倍，从而平衡XX雌雄同体和XO雄性之间的基因表达。 X染色体结构被DCC亚基的突变破坏。使用X染色体涂料荧光显微镜，我们发现当将异染色质锚定至核层的机制存在缺陷时，X染色体的结构和亚核的定位也被破坏。令人惊讶的是，X染色体的异色左端比缺少异色锚点的基因丰富的中间区域受到的影响要小。 X染色体结构和亚核定位的这些变化伴随有小但显着水平的X连锁基因的抑制，如通过RNA-seq测得的，在DCC定位和DCC介导的组蛋白修饰中没有任何可观察到的缺陷。我们提出了一个模型，其中X左臂上的异色系链与DCC配合以压缩X染色体并在外围重新定位，从而有助于基因抑制。作者简介从单个人类细胞核中分离出的DNA如果伸展开，将长3米。此数量的DNA必须包装到一个核中，该核要小几个数量级。活性基因的DNA倾向于在核内内部松散堆积和定位，而无效基因的DNA倾向于在核外围附近紧密堆积和定位。我们使用线虫秀丽隐杆线虫（Caenorhabditis elegans）的X染色体调节作为模型研究了DNA紧实和核定位对基因表达水平的影响。在这种生物中，雌雄同体有两个X染色体，而雄性只有一个。在雌雄同体的两个X染色体上的基因表达水平是雄性X的一半，因此，两个X一起表达的基因产物与雄性X中的单个X一样多。我们发现，雌雄同体X染色体左端的沉默区域被束缚在核外围，这些束缚被用于构建紧凑的染色体结构。如果此过程有缺陷，则基因表达水平会提高，但低于两倍。这些结果表明染色体紧缩和核定位有助于影响基因表达水平，但其他机制也必须起作用。

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