Phase-separated nuclear bodies of nucleoporin fusions, SET-NUP214 and NUP98-HOXA9, promote condensation of MLL1 and CRM1 to activate target genes
Phase-separated nuclear bodies of nucleoporin fusions, SET-NUP214 and NUP98-HOXA9, promote condensation of MLL1 and CRM1 to activate target genes
复制标题
核孔蛋白融合物SET-NUP214和NUP98-HOXA9的相分离核体促进MLL1和CRM1缩合以激活靶基因
DOI：
10.1101/2022.05.24.493212
复制
发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Yoneda Yoshihiro
中科院分区：
文献类型：
--
作者：
Oka Masahiro;Otani Mayumi;Miyamoto Yoichi;Adachi Jun;Tomonaga Takeshi;Asally Munehiro;Ohkawa Yasuyuki;Yoneda Yoshihiro
核孔蛋白NUP98和NUP214形成嵌合融合蛋白，组装成相分离的核体。然而，这些核体的功能和生理意义在很大程度上仍不清楚。此前，我们报道了NUP98-HOXA9和SET-NUP214都是通过染色质结合的核出口受体CRM1被招募到HOX簇区的。在这里，我们发现这些核体促进混合系白血病1(MLL1)的缩合，这是一种组蛋白甲基转移酶，对维持HOX基因的表达是必不可少的。我们的分析表明，SET-NUP214和CRM1与MLL1紧密结合形成核体，并共同定位于染色质上。我们还发现MLL1和CRM1被募集到NUP98-HOXA9的核体中，并且NUP98-HOXA9/CRM1/MLL1复合体聚集在其靶基因位点上，包括HOX簇和MEIS1。这些现象在NUP98-HOXA9的相分离缺陷突变体和非DNA结合突变体中没有观察到。总之，这些结果表明，相分离和适当的核孔素融合到特定的位点都可以通过促进MLL1和CRM1的缩合来增强广泛的靶基因的激活。
Nucleoporins NUP98 and NUP214 form chimeric fusion proteins that assemble into phase-separated nuclear bodies. However, the function and physiological significance of these nuclear bodies remain largely unknown. Previously, we reported that both NUP98-HOXA9 and SET-NUP214 are recruited toHOXcluster regions via chromatin-bound CRM1, a nuclear export receptor . Here, we show that these nuclear bodies promote the condensation of mixed lineage leukemia 1 (MLL1), a histone methyltransferase which is essential for the maintenance ofHOXgene expression. Our analysis revealed that SET-NUP214 and CRM1 robustly associate with MLL1 to form nuclear bodies and are colocalized on chromatin. We also showed that MLL1 and CRM1 are recruited to the nuclear bodies of NUP98-HOXA9 and that the NUP98-HOXA9/CRM1/MLL1 complex accumulates on its target gene loci, includingHOXclusters andMEIS1. These phenomena were not observed in phase-separation–deficient mutants or non-DNA-binding mutants of NUP98-HOXA9. Collectively, these results show that both phase separation and proper targeting of nucleoporin fusions to specific sites could enhance the activation of a wide range of target genes by promoting the condensation of MLL1 and CRM1.
登录
查看更多内容
影响因子：
64.5
作者：
Yokoyama, A;Somervaille, TCP;Cleary, ML
通讯作者：
Cleary, ML
影响因子：
16.8
作者：
Terlecki-Zaniewicz, Stefan;Humer, Theresa;Grebien, Florian
通讯作者：
Grebien, Florian
影响因子：
3.9
作者：
Turner JG;Dawson J;Emmons MF;Cubitt CL;Kauffman M;Shacham S;Hazlehurst LA;Sullivan DM
通讯作者：
Sullivan DM
影响因子：
13.8
作者：
Matkar, Smita;Thiel, Austin;Hua, Xianxin
通讯作者：
Hua, Xianxin
影响因子：
50.3
作者：
Xu H;Valerio DG;Eisold ME;Sinha A;Koche RP;Hu W;Chen CW;Chu SH;Brien GL;Park CY;Hsieh JJ;Ernst P;Armstrong SA
通讯作者：
Armstrong SA