Nup98 recruits the Wdr82-Set1A/COMPASS complex to promoters to regulate H3K4 trimethylation in hematopoietic progenitor cells.
Nup98 recruits the Wdr82-Set1A/COMPASS complex to promoters to regulate H3K4 trimethylation in hematopoietic progenitor cells.
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DOI：
10.1101/gad.306753.117
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发表时间：
2017-11-15
影响因子：
10.5
通讯作者：
Hetzer MW
中科院分区：
文献类型：
--
作者：
Franks TM;McCloskey A;Shokirev MN;Benner C;Rathore A;Hetzer MW
在这项研究中，弗兰克斯等人探究了Nup98调控基因表达的潜在机制。他们表明，在造血细胞中，Nup98主要结合在转录起始位点，以招募Wdr82 - Set1A/COMPASS复合物，该复合物是组蛋白3赖氨酸4三甲基（H3K4me3）激活标记沉积所必需的，并且一种与侵袭性急性髓系白血病（AML）有关的Nup98融合蛋白的表达会导致H3K4me3在异常区域的错误定位以及由于Wdr82/Set1A活性异常而使相关基因上调。
近期研究表明，一部分核孔蛋白（Nups）能够从核孔复合物上脱离并进入细胞核内部以调控转录。一种这样的动态核孔蛋白，称为Nup98，在健康细胞中与基因激活有关，并且在急性髓系白血病（AML）患者中发生突变时已被证明会驱动白血病发生。在此我们表明，在造血细胞中，Nup98主要结合在转录起始位点以招募Wdr82 - Set1A/COMPASS（与Set1相关的蛋白质复合物）复合物，该复合物是组蛋白3赖氨酸4三甲基（H3K4me3）激活标记沉积所必需的。Nup98或Wdr82的缺失会消除Set1A向染色质的招募，并随后消除相邻启动子处的H3K4me3。此外，一种与侵袭性AML有关的Nup98融合蛋白的表达会导致H3K4me3在异常区域的错误定位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一种功能，并为Nup98白血病融合蛋白促进AML的机制提供了见解。
In this study, Franks et al. investigated the mechanisms underlying how Nup98 regulates gene expression. They show that in hematopoietic cells, Nup98 binds predominantly to transcription start sites to recruit the Wdr82–Set1A/COMPASS complex, which is required for deposition of the histone 3 Lys4 trimethyl (H3K4me3)-activating mark, and expression of a Nup98 fusion protein implicated in aggressive AML causes mislocalization of H3K4me3 at aberrant regions and up-regulation of associated genes due to aberrant Wdr82/Set1A activity. 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.
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