Consequences of aneuploidy in human fibroblasts with trisomy 21.
Consequences of aneuploidy in human fibroblasts with trisomy 21.
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DOI：
10.1073/pnas.2014723118
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发表时间：
2021-02-09
影响因子：
11.1
通讯作者：
Torres EM
中科院分区：
文献类型：
--
作者：
Hwang S;Cavaliere P;Li R;Zhu LJ;Dephoure N;Torres EM
染色体数量异常或非整倍体导致大多数自然流产，因为在发育过程中单个染色体的错误分离通常是致命的。只有患有导致唐氏综合症的21三体的个体才能活到成年，但会表现出认知障碍、白血病、自身免疫性疾病的风险增加以及与早衰相关的临床症状。非整倍体影响细胞功能导致唐氏综合症的机制尚不清楚。我们的研究表明，非整倍体会导致唐氏综合症患者的细胞出现几种缺陷。这些包括基因和蛋白质表达增加，生存能力降低，以及对丝氨酸增殖的依赖性增加。我们的研究建立了非整倍性的关键作用，独立于三倍基因身份，在驱动细胞缺陷与21三体相关。21号染色体的额外拷贝会导致唐氏综合症，这是人类最常见的遗传疾病。在这种综合征中，与三倍体基因的身份无关的非整倍体相关病理的机制尚未得到很好的定义。为了表征21三体细胞的非整倍体驱动表型，我们对患有Patau（13三体）、Edwards（18三体）或唐氏综合征的人原代成纤维细胞进行了全球转录组、蛋白质组和表型分析。在所有三体中，mRNA和蛋白质水平平均增加了1.5倍，大分子复合物亚基富集的蛋白质亚群显示出转录后调控的迹象。这些结果支持缺乏证据证明在人类常染色体中广泛存在剂量补偿或染色体结构域失调。此外，我们发现在21三体细胞中存在几种非整倍体相关表型，包括较低的活力和对丝氨酸驱动的脂质合成的依赖性增加。我们的研究建立了非整倍性的关键作用，独立于三倍基因身份，在驱动细胞缺陷与21三体相关。
An abnormal number of chromosomes or aneuploidy accounts for most spontaneous abortions, as missegregation of a single chromosome during development is often lethal. Only individuals with trisomy 21, which causes Down syndrome, can live to adulthood but show cognitive disabilities, increased risk for leukemias, autoimmune disorders, and clinical symptoms associated with premature aging. The mechanisms by which aneuploidy affects cellular function to cause Down syndrome are not understood. Our studies revealed that aneuploidy causes several defects in cells from individuals with Down syndrome. These include increased gene and protein expression, lower viability, and increased dependency on serine to proliferate. Our studies establish a critical role of aneuploidy, independent of triplicated gene identity, in driving cellular defects associated with trisomy 21. An extra copy of chromosome 21 causes Down syndrome, the most common genetic disease in humans. The mechanisms contributing to aneuploidy-related pathologies in this syndrome, independent of the identity of the triplicated genes, are not well defined. To characterize aneuploidy-driven phenotypes in trisomy 21 cells, we performed global transcriptome, proteome, and phenotypic analyses of primary human fibroblasts from individuals with Patau (trisomy 13), Edwards (trisomy 18), or Down syndromes. On average, mRNA and protein levels were increased by 1.5-fold in all trisomies, with a subset of proteins enriched for subunits of macromolecular complexes showing signs of posttranscriptional regulation. These results support the lack of evidence for widespread dosage compensation or dysregulation of chromosomal domains in human autosomes. Furthermore, we show that several aneuploidy-associated phenotypes are present in trisomy 21 cells, including lower viability and increased dependency on serine-driven lipid synthesis. Our studies establish a critical role of aneuploidy, independent of triplicated gene identity, in driving cellular defects associated with trisomy 21.
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DOI：
10.1038/nrm2718
发表时间：
2009-07
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
7.3
作者：
Disteche CM
通讯作者：
Disteche CM
DOI：
10.1093/database/bau009
发表时间：
2014
期刊：
Database : the journal of biological databases and curation
影响因子：
--
作者：
Scarpato M;Esposito R;Evangelista D;Aprile M;Ambrosio MR;Angelini C;Ciccodicola A;Costa V
通讯作者：
Costa V
影响因子：
7
作者：
Harrow J;Frankish A;Gonzalez JM;Tapanari E;Diekhans M;Kokocinski F;Aken BL;Barrell D;Zadissa A;Searle S;Barnes I;Bignell A;Boychenko V;Hunt T;Kay M;Mukherjee G;Rajan J;Despacio-Reyes G;Saunders G;Steward C;Harte R;Lin M;Howald C;Tanzer A;Derrien T;Chrast J;Walters N;Balasubramanian S;Pei B;Tress M;Rodriguez JM;Ezkurdia I;van Baren J;Brent M;Haussler D;Kellis M;Valencia A;Reymond A;Gerstein M;Guigó R;Hubbard TJ
通讯作者：
Hubbard TJ
影响因子：
3.7
作者：
Gonzales PK;Roberts CM;Fonte V;Jacobsen C;Stein GH;Link CD
通讯作者：
Link CD