Department of Cell Biology, Duke Medical Center, Durham, NC, 27710, USA.
Duke Cancer Institute, Duke University, Durham, NC, 27710, USA.
Nat Commun. 2020 May 25;11(1):2606. doi: 10.1038/s41467-020-16394-3.
Nucleoporin proteins (Nups) have been proposed to mediate spatial and temporal chromatin organization during gene regulation. Nevertheless, the molecular mechanisms in mammalian cells are not well understood. Here, we report that Nucleoporin 153 (NUP153) interacts with the chromatin architectural proteins, CTCF and cohesin, and mediates their binding across cis-regulatory elements and TAD boundaries in mouse embryonic stem (ES) cells. NUP153 depletion results in altered CTCF and cohesin binding and differential gene expression - specifically at the bivalent developmental genes. To investigate the molecular mechanism, we utilize epidermal growth factor (EGF)-inducible immediate early genes (IEGs). We find that NUP153 controls CTCF and cohesin binding at the cis-regulatory elements and POL II pausing during the basal state. Furthermore, efficient IEG transcription relies on NUP153. We propose that NUP153 links the nuclear pore complex (NPC) to chromatin architecture allowing genes that are poised to respond rapidly to developmental cues to be properly modulated.
核孔蛋白（Nups）被提出在基因调控过程中介导时空染色质组织。然而，哺乳动物细胞中的分子机制尚不清楚。在这里，我们报告说核孔蛋白 153（NUP153）与染色质结构蛋白 CTCF 和黏连蛋白相互作用，并介导它们在小鼠胚胎干细胞（ES）细胞中跨越顺式调控元件和 TAD 边界的结合。NUP153 耗竭导致 CTCF 和黏连蛋白结合和差异基因表达改变 - 特别是在双价发育基因上。为了研究分子机制，我们利用表皮生长因子（EGF）诱导的即刻早期基因（IEGs）。我们发现 NUP153 在基础状态下控制顺式调控元件和 POL II 暂停处的 CTCF 和黏连蛋白结合。此外，高效的 IEG 转录依赖于 NUP153。我们提出 NUP153 将核孔复合物（NPC）与染色质结构联系起来，使准备对发育信号做出快速反应的基因能够得到适当的调节。
