Aberrant splicing and defective mRNA production induced by somatic spliceosome mutations in myelodysplasia.
Aberrant splicing and defective mRNA production induced by somatic spliceosome mutations in myelodysplasia.
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DOI：
10.1038/s41467-018-06063-x
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发表时间：
2018-09-07
影响因子：
16.6
通讯作者：
Cazzola M
中科院分区：
文献类型：
--
作者：
Shiozawa Y;Malcovati L;Gallì A;Sato-Otsubo A;Kataoka K;Sato Y;Watatani Y;Suzuki H;Yoshizato T;Yoshida K;Sanada M;Makishima H;Shiraishi Y;Chiba K;Hellström-Lindberg E;Miyano S;Ogawa S;Cazzola M
剪接体突变常见于骨髓增生异常。由这些突变诱导的剪接改变、它们的精确靶点以及在转录水平上的作用尚未完全阐明。在这里，我们报告了265例骨髓增生异常患者骨髓样本的转录组学分析，随后使用CRISPR/Cas9介导的基因编辑进行验证，并评估无义介导的衰变易感性。小，但广泛的减少内含子保留亚型是最常见的剪接改变SF 3B 1突变的样品。SF 3B 1突变还与3′剪接位点改变相关，导致典型转录物的最显著减少。靶基因包括肿瘤抑制基因和线粒体铁代谢或血红素生物合成基因。选择性外显子使用在SRSF 2和U2 AF 1突变样品中占主导地位。携带提前终止密码子的EZH 2隐蔽外显子的使用在SRSF 2和U2 AF 1突变的样品中均增加。我们的研究揭示了剪接改变的景观和各种剪接体突变的精确靶点。剪接机制的突变可能在脊髓发育不良中起重要作用。在这里，作者描述了剪接因子基因突变在骨髓增生异常和报告肿瘤抑制，表观遗传，铁代谢和血红素生物合成基因作为其目标。
Spliceosome mutations are frequently found in myelodysplasia. Splicing alterations induced by these mutations, their precise targets, and the effect at the transcript level have not been fully elucidated. Here we report transcriptomic analyses of 265 bone marrow samples from myelodysplasia patients, followed by a validation using CRISPR/Cas9-mediated gene editing and an assessment of nonsense-mediated decay susceptibility. Small but widespread reduction of intron-retaining isoforms is the most frequent splicing alteration in SF3B1-mutated samples. SF3B1 mutation is also associated with 3′ splice site alterations, leading to the most pronounced reduction of canonical transcripts. Target genes include tumor suppressors and genes of mitochondrial iron metabolism or heme biosynthesis. Alternative exon usage is predominant in SRSF2- and U2AF1-mutated samples. Usage of an EZH2 cryptic exon harboring a premature termination codon is increased in both SRSF2- and U2AF1-mutated samples. Our study reveals a landscape of splicing alterations and precise targets of various spliceosome mutations. Mutations to the splicing machinery may have an important role in myelodysplasia. Here, the authors describe splicing factor gene mutations in myelodysplasia and report tumor suppressor, epigenetic, iron metabolism and heme biosynthesis genes as their targets.
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影响因子：
11.4
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通讯作者：
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影响因子：
50.3
作者：
Figueroa ME;Abdel-Wahab O;Lu C;Ward PS;Patel J;Shih A;Li Y;Bhagwat N;Vasanthakumar A;Fernandez HF;Tallman MS;Sun Z;Wolniak K;Peeters JK;Liu W;Choe SE;Fantin VR;Paietta E;Löwenberg B;Licht JD;Godley LA;Delwel R;Valk PJ;Thompson CB;Levine RL;Melnick A
通讯作者：
Melnick A
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7
作者：
Brooks, Angela N.;Yang, Li;Graveley, Brenton R.
通讯作者：
Graveley, Brenton R.
影响因子：
11.8
作者：
Boothby, Thomas C.;Zipper, Richard S.;Wolniak, Stephen M.
通讯作者：
Wolniak, Stephen M.
影响因子：
8.8
作者：
Darman, Rachel B.;Seiler, Michael;Buonamici, Silvia
通讯作者：
Buonamici, Silvia