GRWD1-WDR5-MLL2 Epigenetic Complex Mediates H3K4me3 Mark and Is Essential for Kaposi's Sarcoma-Associated Herpesvirus-Induced Cellular Transformation.
GRWD1-WDR5-MLL2 Epigenetic Complex Mediates H3K4me3 Mark and Is Essential for Kaposi's Sarcoma-Associated Herpesvirus-Induced Cellular Transformation.
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DOI：
10.1128/mbio.03431-21
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发表时间：
2021-12-21
期刊：
影响因子：
6.4
通讯作者：
Gao SJ
中科院分区：
文献类型：
--
作者：
Wei S;Lu S;Liang L;Wang X;Li W;Li T;Chen L;Ju E;Zhang X;Lai Z;Huang Y;Lu X;Gao SJ
卡波西肉瘤相关疱疹病毒(KSHV)感染与多种癌症有因果关系。KSHV诱导肿瘤发生的机制尚不清楚。通过在KSHV诱导的原代细胞转化模型中进行CRISPR-Cas9筛选，我们确定了KSHV诱导的细胞转化所必需的表观遗传调控因子。对前9个基因的TCGA数据集的检查，包括富含谷氨酸的WD重复序列1(GRWD1)，一个受KSHV上调的WD40家族蛋白，对KSHV转化的细胞(KMM)的细胞增殖和存活有积极影响，但对匹配的原代细胞(MM)却没有，发现了它们的表达对多种类型癌症中患者生存的预测价值。与MM细胞相比，我们揭示了KMM细胞包括H3K4me3表观遗传活性标记在内的整体表观遗传重塑。GRWD1基因的敲除抑制了KMM细胞的增殖、转化和肿瘤形成，并导致KMM细胞中H3K4me3基因的表达下调。GRWD1与H3K4甲基转移酶复合体的核心蛋白WD重复结构域5(WDR5)和几种H3K4me3甲基转移酶相互作用，包括髓系白血病2(MLL2)。WDR5和MLL2基因的敲除导致GRWD1基因敲除，导致H3K4me3标记的全局减少，并改变了相似的基因集的表达。转录组测序(RNA-SEQ)和染色质免疫沉淀测序(CHIP-SEQ)进一步分析了受GRWD1、WDR5和MLL2调控的共同和不同的细胞基因和途径。这些结果表明，KSHV劫持了GRWD1-WDR5-ML12表观遗传复合体来调节特定基因的H3K4me3甲基化，这是KSHV诱导细胞转化所必需的。我们的工作已经确定了一种表观遗传复合体作为治疗KSHV诱导的癌症的新靶点。
Infection by Kaposi’s sarcoma-associated herpesvirus (KSHV) is causally associated with numerous cancers. The mechanism of KSHV-induced oncogenesis remains unclear. By performing a CRISPR-Cas9 screening in a model of KSHV-induced cellular transformation of primary cells, we identified epigenetic regulators that were essential for KSHV-induced cellular transformation. Examination of TCGA data sets of the top 9 genes, including glutamate-rich WD repeat containing 1 (GRWD1), a WD40 family protein upregulated by KSHV, that had positive effects on cell proliferation and survival of KSHV-transformed cells (KMM) but not the matched primary cells (MM), uncovered the predictive values of their expressions for patient survival in numerous types of cancer. We revealed global epigenetic remodeling including H3K4me3 epigenetic active mark in KMM cells compared to MM cells. Knockdown of GRWD1 inhibited cell proliferation, cellular transformation, and tumor formation and caused downregulation of global H3K4me3 mark in KMM cells. GRWD1 interacted with WD repeat domain 5 (WDR5), the core protein of H3K4 methyltransferase complex, and several H3K4me3 methyltransferases, including myeloid leukemia 2 (MLL2). Knockdown of WDR5 and MLL2 phenocopied GRWD1 knockdown, caused global reduction of H3K4me3 mark, and altered the expression of similar sets of genes. Transcriptome sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) analyses further identified common and distinct cellular genes and pathways that were regulated by GRWD1, WDR5, and MLL2. These results indicate that KSHV hijacks the GRWD1-WDR5-MLL2 epigenetic complex to regulate H3K4me3 methylation of specific genes, which is essential for KSHV-induced cellular transformation. Our work has identified an epigenetic complex as a novel therapeutic target for KSHV-induced cancers.
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影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
影响因子：
16.8
作者：
Hu D;Garruss AS;Gao X;Morgan MA;Cook M;Smith ER;Shilatifard A
通讯作者：
Shilatifard A
影响因子：
6.7
作者：
Günther T;Grundhoff A
通讯作者：
Grundhoff A
DOI：
10.1073/pnas.011404098
发表时间：
2001-01-02
影响因子：
11.1
作者：
Li, C;Wong, WH
通讯作者：
Wong, WH
通过致癌病毒进行宿主的表观遗传修饰。
影响因子：
8.8
作者：
Flanagan, J M
通讯作者：
Flanagan, J M