iPS细胞在重编程过程中可引起线粒体基因组突变

sunsong7

来自柏林的消息，马克斯普朗克分子遗传学研究所发现所有的重编程细胞的线粒体基因组中存在与起始细胞不同的基因突变，而且所测试的每个iPS细胞发生突变的数量存在显著差异，这些突变是遗传编码的单个字母改变而，没有引起大规模序列重排。6 q- A" j6 R: Y. N- o0 L
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Cellular Power Plant Genome Mutates When Reprogrammed: Genetic Changes in Mitochondrial Genome of Human Induced Pluripotent Stem Cells
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( W8 l+ }1 u' o. [3 oScienceDaily (July 29, 2011) — Induced pluripotent stem cells (iPS cells) are truly talented multi-taskers. They can reproduce almost all cell types and thus offer great hope in the fight against diseases like Alzheimer's and Parkinson's. However, it would appear that their use is not entirely without risk: during the reprogramming of body cells into iPS cells, disease-causing mutations can creep into the genetic material. The genome of the mitochondria -- the cell's protein factories -- is particularly vulnerable to such changes.$ d6 }8 j1 i% q

: J! k% [' o! X, l- rMutations in the mitochondrial genome of iPS cells (Credit: © MPI for Molecular Genetics)0 B, x6 [$ C) n4 v4 Q0 E! o" a" {
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This phenomenon has been discovered by researchers at the Max Planck Institute for Molecular Genetics in Berlin. The scientists encountered mutations in the mitochondrial genome of iPS cells. Because such genetic mutations can cause diseases, the cells should be tested for such mutations before being used for clinical applications.4 w& Z$ o: ~7 E' m" A
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A lot of hope is riding on induced pluripotent stem cells (iPS cells). Because they can be generated individually for every single person, they are expected to enable the development of tailor-made therapies that do not run the risk of triggering rejection reactions. iPS cells also offer a promising solution for drug screening, as researchers can generate different cell types such as liver cells from them, on which they can then test the effect of substances. iPS cells can be generated from adult body cells using the technique of "cellular reprogramming." The method raises no ethical concerns as it does not involve the destruction of embryos.
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However, these promising cells are also associated with certain risks. Disease-causing mutations can also arise during the reprogramming of the body cells. The genetic material in the mitochondria is particularly vulnerable to changes in the genetic code. The question as to whether such mutations arise as a result of the reprogramming process had not previously been investigated.
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A cooperative research study involving two research groups from the Max Planck Institute for Molecular Genetics in Berlin has now carried out a search for mutations in the mitochondrial genome of iPS cells. James Adjaye's research group recently discovered that the mitochondria rejuvenate in the course of reprogramming. Working in cooperation with Bernd Timmermann's Next Generation Sequencing research group, Adjaye's team has succeeded in showing that genetic mutations exist in the mitochondrial genome of all reprogrammed cells that were not present in the original cells. The amount of mutations varies significantly between the individual iPS cells examined. In all cases, the changes did not involve large-scale rearrangements but rather modifications of single letters in the genetic code.
0 b* a" V7 j( Whttp://www.sciencedaily.com/releases/2011/07/110728082309.htm

song2086

不是新闻，线粒体DNA（mtDNA）是裸露的，没有组蛋白的包裹和保护，·因此环境因素如射线，自由基可以直接损伤线粒体DNA(mtDNA）,而核DNA由于组蛋白将DNA缠绕形成核小体，最后缠绕形成染色体，射线，自由基首先导致组蛋白受伤，因此IPS细胞重编程过程中线粒体DNA可能只是常见现象。

FreeCell

回复 song2086 的帖子! {3 Q8 d7 F- z) J( z# \8 x/ l8 y

& \0 l# h! r3 ~' d8 j$ i1 E/ \嘻嘻，不是吧，如此一来后代的线粒体还能呼吸吗，原核生物岂不更没得活路？

song2086

回复 FreeCell 的帖子
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可以修复吗！但是mtDNA比核DNA突变率高，这是大家早就发现的事实

FreeCell

回复 song2086 的帖子
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问题是如果能修好的话，不该发现iPSC细胞线粒体的基因组个个都不一样吧？

song2086

回复 FreeCell 的帖子
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  |+ d' ~! ~" Z一个氨基酸有多个密码子，密码子的第二和第三位碱基突变，一般氨基酸不改变，即使氨基酸改变，导致氨基酸置换，同类氨基酸也不影响蛋白质的高级结构，只要不导致碱基缺失或插入突变，危害不大，有时还可以导致进化呢！！

FreeCell

回复 song2086 的帖子
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人家的问题是 “The genetic material in the mitochondria is particularly vulnerable to changes in the genetic code. The question as to whether such mutations arise as a result of the reprogramming process had not previously been investigated.”
/ ]  E9 h; E) m# o& k" f& ]如果iPSC线粒体基因组突变在正常范围的话那敢情好，恐怕情况并非如此

zorro

回复 sunsong7 的帖子% ^3 L. z; e( Z+ |, D

- E* }. a4 d  d5 h# u有原文不 谢谢

sylar.wy

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! _' `$ G' `7 `6 w是这篇么？ 新手- - 还不太懂。。今年刚研一，还没开学。
1 {. X. ?9 y. VStem Cells. 2011 Jul 5. doi: 10.1002/stem.683. [Epub ahead of print]
  L4 X; o6 m3 k7 Y6 YHuman iPSCs Harbor Homoplasmic and Heteroplasmic Mitochondrial DNA Mutations While Maintaining hESC-Like Metabolic Reprogramming.
8 h  y! ]7 l$ g" ?0 Q7 J# Z% sPrigione A, Lichtner B, Kuhl H, Struys EA, Wamelink M, Lehrach H, Ralser M, Timmermann B, Adjaye J.
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Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany. prigione@molgen.mpg.de.
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Human induced pluripotent stem cells (iPSCs) have been recently found to harbor genomic alterations. However, the integrity of mitochondrial DNA (mtDNA) within reprogrammed cells has yet to be investigated. mtDNA mutations occur at a high rate and are believed to contribute to the pathology of a number of human disorders. Furthermore, lack of mtDNA integrity may alter cellular bioenergetics and limit efficient differentiation. We previously demonstrated that the derivation of iPSCs is associated with mitochondrial remodeling and a metabolic switch towards glycolysis. Here, we aimed to determine the consequences of reprogramming on mtDNA integrity. Massively parallel pyrosequencing of mtDNA revealed that human iPSCs derived from young healthy donors harbored single base mtDNA mutations (substitutions, insertions, and deletions), both homoplasmic (in all mtDNA molecules) and heteroplasmic (in a fraction of mtDNAs). Interestingly, the level of heteroplasmy varied among iPSC lines derived from the same parental fibroblasts. This phenomenon could potentially be exploited for the generation of mtDNA mutation-free iPSCs from patients with mtDNA disorders. By integrating transcriptional, metabolic, and functional bioenergetic data, we unveiled that iPSC lines bearing different mtDNA mutational loads maintained a consistent hESC-like reprogramming of energy metabolism. This included over-expression of glycolytic enzymes, increased amount of G6P, and elevated protein expression of PDK1, which re-routes the bioenergetic flux towards glycolysis. Overall, although the mtDNA mutations within our iPSCs did not affect the reprogramming-associated metabolic modulation, the occurrence of pathogenic mtDNA modifications might be an important aspect to monitor when characterizing iPSC lines.

sylar.wy

回复 zorro 的帖子
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原文找到了。。呵呵
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