H3.3K27M-induced chromatin changes drive ectopic replication through misregulation of the JNK pathway in C. elegans
H3.3K27M-induced chromatin changes drive ectopic replication through misregulation of the JNK pathway in C. elegans
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DOI：
10.1038/s41467-019-10404-9
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发表时间：
2019-06-07
影响因子：
16.6
通讯作者：
Steiner, Florian A.
中科院分区：
文献类型：
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作者：
Delaney, Kamila;Strobino, Maude;Steiner, Florian A.
组蛋白H3.3中赖氨酸27被蛋氨酸取代是最近发现的儿童高级别胶质瘤的驱动突变。突变细胞显示H3K27三甲基化（H3K27me3）水平降低和分布改变。这些染色质变化如何在全基因组范围内建立并导致肿瘤发生尚不清楚。本研究表明，h3.3 k27m介导的H3K27me3分布的改变导致秀丽隐杆线虫生殖细胞的异位DNA复制和细胞周期的进展。通过基因诱导H3.3分布的变化，我们证明H3.3 k27m和预先存在的H3K27me3都以浓度依赖的方式局部拮抗地作用于Polycomb suppression Complex 2 （PRC2）。异染色质的改变导致广泛的基因失调，遗传筛查发现JNK的上调是生殖细胞畸变的潜在原因。此外，JNK抑制抑制了人类肿瘤源性H3.3K27M细胞的复制命运，从而使秀丽隐杆线虫成为鉴定治疗H3.3K27M肿瘤的潜在药物靶点的强大模型。
Substitution of lysine 27 with methionine in histone H3.3 is a recently discovered driver mutation of pediatric high-grade gliomas. Mutant cells show decreased levels and altered distribution of H3K27 trimethylation (H3K27me3). How these chromatin changes are established genome-wide and lead to tumorigenesis remains unclear. Here we show that H3.3K27M-mediated alterations in H3K27me3 distribution result in ectopic DNA replication and cell cycle progression of germ cells in Caenorhabditis elegans. By genetically inducing changes in the H3.3 distribution, we demonstrate that both H3.3K27M and pre-existing H3K27me3 act locally and antagonistically on Polycomb Repressive Complex 2 (PRC2) in a concentration-dependent manner. The heterochromatin changes result in extensive gene misregulation, and genetic screening identified upregulation of JNK as an underlying cause of the germcell aberrations. Moreover, JNK inhibition suppresses the replicative fate in human tumor-derived H3.3K27M cells, thus establishing C. elegans as a powerful model for the identification of potential drug targets for treatment of H3.3K27M tumors.