In the nucleus, chromosomes are hierarchically folded into active (A) and inactive (B) compartments composed of topologically associating domains (TADs). Genomic regions interact with nuclear lamina, termed lamina-associated domains (LADs). However, the molecular mechanisms underlying these 3D chromatin architectures remain incompletely understood. Here, we investigated the role of a potential tumor suppressor, TOP1 Binding Arginine/Serine Rich Protein (TOPORS), in genome organization. In mouse hepatocytes, chromatin interactions between A and B compartments increase and compartmentalization strength is reduced significantly upon Topors knockdown. Correspondingly, strength of TAD boundaries located at A/B borders is weakened. In the absence of TOPORS, chromatin-lamina interactions decrease and the coverage of LADs reduces from 53.31% to 46.52%. Interestingly, these changes in 3D genome are associated with PML nuclear bodies and PML-associated domains (PADs). Moreover, chromatin accessibility is altered predominantly at intergenic regions upon Topors knockdown, including a subset of enhancers. These alterations of chromatin are concordant with transcriptome changes, which are associated with carcinogenesis. Collectively, our findings demonstrate that TOPORS functions as a regulator in chromatin structure, providing novel insight into the architectural roles of tumor suppressors in higher-order genome organization.

中文翻译：

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TOPORS是一种肿瘤抑制蛋白，有助于维持更高阶的染色质结构。

在细胞核中，染色体按层次折叠成由拓扑关联域（TAD）组成的活动（A）和不活动（B）隔室。基因组区域与核层相互作用，称为层相关域（LAD）。但是，这些3D染色质体系结构的分子机制仍不完全清楚。在这里，我们调查了潜在的肿瘤抑制因子TOP1结合精氨酸/富含丝氨酸的蛋白质（TOPORS）在基因组组织中的作用。在小鼠肝细胞中，A和B区室之间的染色质相互作用增加，而Topors敲低后区室化强度显着降低。相应地，位于A / B边界的TAD边界的强度会减弱。在没有TOPORS的情况下，染色质-层板相互作用减少，LAD的覆盖率从53.31％降低至46.52％。有趣的是，3D基因组中的这些变化与PML核体和PML相关域（PAD）相关。此外，染色质可及性主要在Topors敲低后在基因间区域发生改变，包括增强子。染色质的这些改变与转录组的变化一致，而转录组的变化与致癌作用有关。总的来说，我们的发现表明TOPORS在染色质结构中起着调节剂的作用，从而为肿瘤抑制子在高阶基因组组织中的结构作用提供了新颖的见解。染色质的这些改变与转录组的变化一致，而转录组的变化与致癌作用有关。总的来说，我们的研究结果表明TOPORS在染色质结构中起着调节剂的作用，从而为肿瘤抑制子在高阶基因组组织中的结构作用提供了新颖的见解。染色质的这些改变与转录组的变化一致，而转录组的变化与致癌作用有关。总的来说，我们的发现表明TOPORS在染色质结构中起着调节剂的作用，从而为肿瘤抑制子在高阶基因组组织中的结构作用提供了新颖的见解。