Effects of H3.3G34V mutation on genomic H3K36 and H3K27 methylation patterns in isogenic pediatric glioma cells.
Effects of H3.3G34V mutation on genomic H3K36 and H3K27 methylation patterns in isogenic pediatric glioma cells.
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DOI：
10.1186/s40478-020-01092-4
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发表时间：
2020-12-07
影响因子：
7.1
通讯作者：
Saratsis AM
中科院分区：
文献类型：
--
作者：
Huang TY;Piunti A;Qi J;Morgan M;Bartom E;Shilatifard A;Saratsis AM
组蛋白H3.3突变（H3 F3 A）发生在50%的皮质儿童高级别胶质瘤中。该突变用精氨酸或缬氨酸（G34 R/V）取代甘氨酸34，损害了SETD 2活性（H3 K36特异性三甲基转移酶）。因此，相对于野生型，在H3.3G34V核小体上观察到减少的H3 K36 me 3，这有助于基因组不稳定性并驱动与肿瘤发生相关的独特基因表达特征。然而，尚不清楚这种差异性H3 K36 me 3富集是否是由于单独的H3.3G34V突变蛋白。因此，我们着手阐明小儿胶质瘤中H3.3G34V突变蛋白对H3 K36 me 3、H3 K27 me 3和H3.3体外富集的影响。我们发现，多西环素诱导的shRNA敲低编码H3.3G34V蛋白的突变体H3 F3 A导致整个基因组中H3.3G34V富集的损失和H3 K36 me 3富集的增加。敲低后，在敲低前观察到具有最大H3.3G34V和H3 K36 me 3富集的基因座处保持H3.3G34V富集。突变H3.3G34V蛋白在体外的诱导表达不足以诱导在H3.3G34V突变胶质瘤细胞中观察到的基因组H3 K36 me 3富集模式。我们还观察到在表达H3.3G34V的细胞中H3.3G34V和野生型H3.3蛋白的强共富集，以及更大的H3 K27 me 3富集。综上所述，我们的研究证明了H3.3G34V突变蛋白对同基因细胞系中基因组H3 K36 me 3、H3 K27 me 3和H3.3富集模式的影响。
Histone H3.3 mutation (H3F3A) occurs in 50% of cortical pediatric high-grade gliomas. This mutation replaces glycine 34 with arginine or valine (G34R/V), impairing SETD2 activity (H3K36-specific trimethyltransferase). Consequently, reduced H3K36me3 is observed on H3.3G34V nucleosomes relative to wild-type, contributing to genomic instability and driving a distinct gene expression signature associated with tumorigenesis. However, it is not known if this differential H3K36me3 enrichment is due to H3.3G34V mutant protein alone. Therefore, we set to elucidate the effect of H3.3G34V mutant protein in pediatric glioma on H3K36me3, H3K27me3 and H3.3 enrichment in vitro. We found that the doxycycline-inducible shRNA knockdown of mutant H3F3A encoding the H3.3G34V protein resulted in loss of H3.3G34V enrichment and increased H3K36me3 enrichment throughout the genome. After knockdown, H3.3G34V enrichment was preserved at loci observed to have the greatest H3.3G34V and H3K36me3 enrichment prior to knockdown. Induced expression of mutant H3.3G34V protein in vitro was insufficient to induce genomic H3K36me3 enrichment patterns observed in H3.3G34V mutant glioma cells. We also observed strong co-enrichment of H3.3G34V and wild-type H3.3 protein, as well as greater H3K27me3 enrichment, in cells expressing H3.3G34V. Taken together, our study demonstrates the effects of H3.3G34V mutant protein on genomic H3K36me3, H3K27me3 and H3.3 enrichment patterns in isogenic cell lines.
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影响因子：
3.7
作者：
Bax DA;Little SE;Gaspar N;Perryman L;Marshall L;Viana-Pereira M;Jones TA;Williams RD;Grigoriadis A;Vassal G;Workman P;Sheer D;Reis RM;Pearson AD;Hargrave D;Jones C
通讯作者：
Jones C
DOI：
10.1126/science.aac7272
发表时间：
2016-05-13
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Lu C;Jain SU;Hoelper D;Bechet D;Molden RC;Ran L;Murphy D;Venneti S;Hameed M;Pawel BR;Wunder JS;Dickson BC;Lundgren SM;Jani KS;De Jay N;Papillon-Cavanagh S;Andrulis IL;Sawyer SL;Grynspan D;Turcotte RE;Nadaf J;Fahiminiyah S;Muir TW;Majewski J;Thompson CB;Chi P;Garcia BA;Allis CD;Jabado N;Lewis PW
通讯作者：
Lewis PW
影响因子：
12.7
作者：
Korshunov, Andrey;Capper, David;Jones, David T. W.
通讯作者：
Jones, David T. W.
影响因子：
5.6
作者：
Shi L;Shi J;Shi X;Li W;Wen H
通讯作者：
Wen H
影响因子：
82.9
作者：
Piunti A;Hashizume R;Morgan MA;Bartom ET;Horbinski CM;Marshall SA;Rendleman EJ;Ma Q;Takahashi YH;Woodfin AR;Misharin AV;Abshiru NA;Lulla RR;Saratsis AM;Kelleher NL;James CD;Shilatifard A
通讯作者：
Shilatifard A