Franks Tobias M, McCloskey Asako, Shokirev Maxim Nikolaievich, Benner Chris, Rathore Annie, Hetzer Martin W
Laboratory of Molecular and Cellular Biology, Salk Institute for Biological Studies, La Jolla, California 92037, USA.
The Razavi Newman Integrative Genomics and Bioinformatics Core, Salk Institute for Biological Studies, La Jolla, California 92037, USA.
Genes Dev. 2017 Nov 15;31(22):2222-2234. doi: 10.1101/gad.306753.117. Epub 2017 Dec 21.
Recent studies have shown that a subset of nucleoporins (Nups) can detach from the nuclear pore complex and move into the nuclear interior to regulate transcription. One such dynamic Nup, called Nup98, has been implicated in gene activation in healthy cells and has been shown to drive leukemogenesis when mutated in patients with acute myeloid leukemia (AML). Here we show that in hematopoietic cells, Nup98 binds predominantly to transcription start sites to recruit the Wdr82-Set1A/COMPASS (complex of proteins associated with Set1) complex, which is required for deposition of the histone 3 Lys4 trimethyl (H3K4me3)-activating mark. Depletion of Nup98 or Wdr82 abolishes Set1A recruitment to chromatin and subsequently ablates H3K4me3 at adjacent promoters. Furthermore, expression of a Nup98 fusion protein implicated in aggressive AML causes mislocalization of H3K4me3 at abnormal regions and up-regulation of associated genes. Our findings establish a function of Nup98 in hematopoietic gene activation and provide mechanistic insight into which Nup98 leukemic fusion proteins promote AML.
最近的研究表明，一部分核孔蛋白（Nups）能够从核孔复合体上脱离并进入核内以调控转录。一种名为Nup98的动态核孔蛋白就参与了健康细胞中的基因激活过程，并且在急性髓系白血病（AML）患者中发生突变时，已被证明会引发白血病。在此我们表明，在造血细胞中，Nup98主要结合于转录起始位点，以招募Wdr82 - Set1A/COMPASS（与Set1相关的蛋白质复合体）复合体，该复合体是组蛋白3赖氨酸4三甲基化（H3K4me3）激活标记沉积所必需的。Nup98或Wdr82的缺失会消除Set1A对染色质的招募，并随后消除相邻启动子处的H3K4me3。此外，一种与侵袭性AML相关的Nup98融合蛋白的表达会导致H3K4me3在异常区域的定位错误以及相关基因的上调。我们的研究结果确立了Nup98在造血基因激活中的功能，并为Nup98白血病融合蛋白促进AML的机制提供了深入见解。
