Expression in aneuploid Drosophila S2 cells.
Expression in aneuploid Drosophila S2 cells.
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DOI：
10.1371/journal.pbio.1000320
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发表时间：
2010-02-23
期刊：
影响因子：
9.8
通讯作者：
Oliver B
中科院分区：
文献类型：
--
作者：
Zhang Y;Malone JH;Powell SK;Periwal V;Spana E;Macalpine DM;Oliver B
通过对非整倍体雄性果蝇细胞基因拷贝数与基因表达关系的分析，揭示了除X染色体特异性剂量补偿外的一种全局补偿机制。在非整倍体中，大量偏离平衡的基因剂量是高度有害的。然而，我们对非整倍体细胞中基因拷贝数与表达之间的关系知之甚少。我们通过DNA-Seq和RNA-Seq测定了果蝇S2细胞全基因组的拷贝数和转录物丰度（表达）。我们发现S2细胞在基因组的bbbb43 Mb中是非整倍体，主要在1到5个拷贝的范围内，并表现出男性基因型（2条X染色体和4组常染色体，或2X；4A）。X染色体和常染色体均表现出表达剂量补偿。无论实际的基因剂量如何，X染色体的表达都以固定折叠的方式升高。用工程术语来说，系统“预测”由X剂量引起的扰动，而不是对扰动引起的误差作出反应。只有当X剂量为常染色体剂量的一半时，这种前馈调节才能产生精确的剂量补偿。低剂量X染色体补偿不足，高剂量X染色体过度表达。RNAi敲低雄性特异性致死复合体取消了前馈调节。常染色体和X染色体基因均显示符合一级剂量-反应曲线的男性特异性致死无关补偿。我们的数据表明，表达剂量补偿在全基因组范围内抑制了DNA拷贝数改变的影响。对于X染色体，补偿包括固定的和剂量依赖的成分。虽然人们普遍认识到蛋白质编码基因的突变可能会产生有害的后果，但一个人也可能有太多或太少的好东西。除了性染色体外，二倍体生物中的基因都是成对的。基因或染色体拷贝的多余或缺失会导致失衡，从而导致癌症、流产和疾病易感性。我们已经研究了果蝇细胞中基因表达的变化，这些细胞的总拷贝数变化类型是典型的癌症。我们已经比较了常染色体和性染色体的反应，并表明在这两种情况下拷贝数的变化都有一定的补偿。一种反应是普遍的，通过改变转录物丰度来纠正拷贝数的变化。另一种是X染色体特有的，无论基因剂量如何，都能增加表达。我们的数据强调了基因表达平衡对细胞功能的重要性。
Analysis of the relationship between gene copy number and gene expression in aneuploid male Drosophila cells reveals a global compensation mechanism in addition to X chromosome-specific dosage compensation. Extensive departures from balanced gene dose in aneuploids are highly deleterious. However, we know very little about the relationship between gene copy number and expression in aneuploid cells. We determined copy number and transcript abundance (expression) genome-wide in Drosophila S2 cells by DNA-Seq and RNA-Seq. We found that S2 cells are aneuploid for >43 Mb of the genome, primarily in the range of one to five copies, and show a male genotype (∼ two X chromosomes and four sets of autosomes, or 2X;4A). Both X chromosomes and autosomes showed expression dosage compensation. X chromosome expression was elevated in a fixed-fold manner regardless of actual gene dose. In engineering terms, the system “anticipates” the perturbation caused by X dose, rather than responding to an error caused by the perturbation. This feed-forward regulation resulted in precise dosage compensation only when X dose was half of the autosome dose. Insufficient compensation occurred at lower X chromosome dose and excessive expression occurred at higher doses. RNAi knockdown of the Male Specific Lethal complex abolished feed-forward regulation. Both autosome and X chromosome genes show Male Specific Lethal–independent compensation that fits a first order dose-response curve. Our data indicate that expression dosage compensation dampens the effect of altered DNA copy number genome-wide. For the X chromosome, compensation includes fixed and dose-dependent components. While it is widely recognized that mutations in protein coding genes can have harmful consequences, one can also have too much or too little of a good thing. Except for the sex chromosomes, genes come in sets of two in diploid organisms. Extra or missing copies of genes or chromosomes result in an imbalance that can lead to cancers, miscarriages, and disease susceptibility. We have examined what happens to gene expression in Drosophila cells with the types of gross copy number changes that are typical of cancers. We have compared the response of autosomes and sex chromosomes and show that there is some compensation for copy number change in both cases. One response is universal and acts to correct copy number changes by changing transcript abundance. The other is specific to the X chromosome and acts to increase expression regardless of gene dose. Our data highlight how important gene expression balance is for cell function.
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影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
56.9
作者：
Hoskins, Roger A.;Carlson, Joseph W.;Celniker, Susan E.
通讯作者：
Celniker, Susan E.
影响因子：
48
作者：
Kulkarni, Meghana M.;Booker, Matthew;Mathey-Prevot, Bernard
通讯作者：
Mathey-Prevot, Bernard
影响因子：
12.3
作者：
Johnston, R;Wang, B;Eastman, S
通讯作者：
Eastman, S
影响因子：
--
作者：
Gupta V;Parisi M;Sturgill D;Nuttall R;Doctolero M;Dudko OK;Malley JD;Eastman PS;Oliver B
通讯作者：
Oliver B