Laboratory of Nuclear Transport Dynamics, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), 7-6-8 Saito-Asagi, Ibaraki, Osaka 567-0085, Japan; Laboratory of Biomedical Innovation, Graduate School of Pharmaceutical Sciences, Osaka University, 1-3 Yamada-oka, Suita, Osaka 565-0871, Japan.
Laboratory of Nuclear Transport Dynamics, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), 7-6-8 Saito-Asagi, Ibaraki, Osaka 567-0085, Japan.
Cell Rep. 2023 Aug 29;42(8):112884. doi: 10.1016/j.celrep.2023.112884. Epub 2023 Jul 29.
NUP98 and NUP214 form chimeric fusion proteins that assemble into phase-separated nuclear bodies containing CRM1, a nuclear export receptor. However, these nuclear bodies' function in controlling gene expression remains elusive. Here, we demonstrate that the nuclear bodies of NUP98::HOXA9 and SET::NUP214 promote the condensation of mixed lineage leukemia 1 (MLL1), a histone methyltransferase essential for the maintenance of HOX gene expression. These nuclear bodies are robustly associated with MLL1/CRM1 and co-localized on chromatin. Furthermore, whole-genome chromatin-conformation capture analysis reveals that NUP98::HOXA9 induces a drastic alteration in high-order genome structure at target regions concomitant with the generation of chromatin loops and/or rearrangement of topologically associating domains in a phase-separation-dependent manner. Collectively, these results show that the phase-separated nuclear bodies of nucleoporin fusion proteins can enhance the activation of target genes by promoting the condensation of MLL1/CRM1 and rearrangement of the 3D genome structure.
NUP98 和 NUP214 形成嵌合融合蛋白，组装成包含 CRM1 的相分离核体，CRM1 是一种核输出受体。然而，这些核体在控制基因表达方面的功能仍不清楚。在这里，我们证明 NUP98::HOXA9 和 SET::NUP214 的核体促进混合谱系白血病 1 (MLL1) 的凝聚，MLL1 是维持 HOX 基因表达所必需的组蛋白甲基转移酶。这些核体与 MLL1/CRM1 紧密相关，并在染色质上共定位。此外，全基因组染色质构象捕获分析显示，NUP98::HOXA9 诱导靶区高级基因组结构的剧烈改变，伴随着染色质环的产生和/或拓扑关联域的重排，这是一种相分离依赖的方式。总之，这些结果表明核孔融合蛋白的相分离核体可以通过促进 MLL1/CRM1 的凝聚和 3D 基因组结构的重排来增强靶基因的激活。
