mtDNA depletion confers specific gene expression profiles in human cells grown in culture and in xenograft.
mtDNA depletion confers specific gene expression profiles in human cells grown in culture and in xenograft.
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DOI：
10.1186/1471-2164-9-521
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发表时间：
2008-11-03
期刊：
影响因子：
4.4
通讯作者：
Hacia, Joseph G.
中科院分区：
文献类型：
--
作者：
Magda, Darren;Lecane, Philip;Prescott, Julia;Thiemann, Patricia;Ma, Xuan;Dranchak, Patricia K.;Toleno, Donna M.;Ramaswamy, Krishna;Siegmund, Kimberly D.;Hacia, Joseph G.
线粒体和核基因组编码的基因产物之间的相互作用在真核细胞功能中发挥着关键作用。然而，生理条件下线粒体 DNA (mtDNA) 水平对核转录组的影响尚未确定。为了解决这个问题，我们对 A549 肺癌细胞及其在培养物中生长的 mtDNA 耗尽的 ρ0 细胞以及免疫缺陷小鼠中的肿瘤异种移植物的基因表达谱进行了表征。培养的 A549 ρ0 细胞存在呼吸缺陷，并表现出与金属稳态、上皮间质转化起始和葡萄糖醛酸化途径相关的转录物水平增强。一些成熟的 HIF 调节转录物显示出相对于亲本细胞系丰度增加或减少。此外，与异种移植物相比，培养物中的生长对表达谱具有显着更大的影响，包括参与线粒体结构以及有氧和无氧能量代谢的转录本。然而，无论是在体外还是体内，mtDNA 水平解释了在葡萄糖醛酸化、tRNA 合成酶和免疫监视相关途径中转录物表达中观察到的大部分差异。 A549 异种移植物中的 mtDNA 水平还影响参与过氧化物酶体脂质代谢途径的基因的表达，例如 AMACR 和 PHYH。我们已经确定了培养细胞和异种移植物中共有的 mtDNA 依赖性基因表达谱。这些概况表明，线粒体 DNA 耗尽的细胞可以提供信息丰富的模型系统，用于测试选定类别的治疗药物（例如抗血管生成剂）的功效。此外，在培养物和异种移植物中培养的线粒体DNA耗尽的细胞提供了一种强有力的方法来研究正常和病理细胞中线粒体活性与基因表达谱之间的可能关系。
Interactions between the gene products encoded by the mitochondrial and nuclear genomes play critical roles in eukaryotic cellular function. However, the effects mitochondrial DNA (mtDNA) levels have on the nuclear transcriptome have not been defined under physiological conditions. In order to address this issue, we characterized the gene expression profiles of A549 lung cancer cells and their mtDNA-depleted ρ0 counterparts grown in culture and as tumor xenografts in immune-deficient mice. Cultured A549 ρ0 cells were respiration-deficient and showed enhanced levels of transcripts relevant to metal homeostasis, initiation of the epithelial-mesenchymal transition, and glucuronidation pathways. Several well-established HIF-regulated transcripts showed increased or decreased abundance relative to the parental cell line. Furthermore, growth in culture versus xenograft has a significantly greater influence on expression profiles, including transcripts involved in mitochondrial structure and both aerobic and anaerobic energy metabolism. However, both in vitro and in vivo, mtDNA levels explained the majority of the variance observed in the expression of transcripts in glucuronidation, tRNA synthetase, and immune surveillance related pathways. mtDNA levels in A549 xenografts also affected the expression of genes, such as AMACR and PHYH, involved in peroxisomal lipid metabolic pathways. We have identified mtDNA-dependent gene expression profiles that are shared in cultured cells and in xenografts. These profiles indicate that mtDNA-depleted cells could provide informative model systems for the testing the efficacy of select classes of therapeutics, such as anti-angiogenesis agents. Furthermore, mtDNA-depleted cells grown culture and in xenografts provide a powerful means to investigate possible relationships between mitochondrial activity and gene expression profiles in normal and pathological cells.
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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：
4.3
作者：
Di Paola, Marco;Lorusso, Michele
通讯作者：
Lorusso, Michele
影响因子：
4.8
作者：
Arnould, T;Mercy, L;Raes, M
通讯作者：
Raes, M
影响因子：
11.2
作者：
Carroll, Veronica A.;Ashcroft, Margaret
通讯作者：
Ashcroft, Margaret
影响因子：
3.5
作者：
Gilkerson, RW;Margineantu, DH;Selker, JML
通讯作者：
Selker, JML