Meiotic behavior of aneuploid chromatin in mouse models of Down syndrome.
Meiotic behavior of aneuploid chromatin in mouse models of Down syndrome.
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DOI：
10.1007/s00412-009-0230-8
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发表时间：
2009-12
期刊：
影响因子：
1.6
通讯作者：
Handel MA
中科院分区：
文献类型：
--
作者：
Reinholdt LG;Czechanski A;Kamdar S;King BL;Sun F;Handel MA
在减数分裂期间，非整倍体导致染色体轴不配对，经常伴有不孕症。我们之前使用三只唐氏综合症小鼠模型表明，是一条额外的染色体，而不是额外的基因剂量，与男性不育和减数分裂后宝石细胞的缺失有关。在这里，我们验证了非整倍体片段在减数分裂期间被差异修饰和表达的假设，这取决于它们是否作为额外的染色体存在。在所有三体模型中，三体区域都缺少配对伙伴，但在一种情况下，精母细胞有一条额外的（未配对的）染色体，而另外两种模型涉及三体区域的易位，而不是额外的染色体。一条额外的未配对染色体总是被组蛋白H2AX磷酸化修饰，缺乏RNA PolII。但是对于附着在配对染色体上的三体区域，这些蛋白质修饰的组装受到三体区域相对于着丝粒的位置和未配对的染色质的物理范围的影响。对睾丸基因表达的分析表明，单靠额外的拷贝数不足以使三体间基因减数分裂上调。此外，令人意外的是，减数分裂基因沉默染色质修饰的存在并不足以下调未配对三体染色质中的基因。因此，细胞学上可见的减数分裂染色质修饰不太可能直接涉及DS模型的不育与生育。最后，额外的未配对染色体的存在，而不是额外的（三体）基因的存在，导致精母细胞中转录的全局失调。这些结果揭示了一个额外的染色体，而不是三体基因剂量，影响减数分裂进程和不孕症的机制。
Aneuploidy, which leads to unpaired chromosomal axes during meiosis, is frequently accompanied by infertility. We previously showed, using three mouse models of Down syndrome, that it is an extra chromosome, but not extra gene dose, that is associated with male infertility and virtual absence of post-meiotic gem cells. Here we test the hypothesis that aneuploid segments are differentially modified and expressed during meiosis, depending on whether they are present as an extra chromosome or not. In all three models examined, the trisomic region lacks a pairing partner, but in one case, spermatocytes have an extra (and unpaired) chromosome, while the two other models involve translocation of the trisomic region rather than an extra chromosome. An extra unpaired chromosome was always modified by phosphorylation of histone H2AX and lacked RNA PolII. But in the case of trisomic regions attached to a paired chromosome, assembly of these protein modifications was affected by the position of a trisomic region relative to a centromere and the physical extent of the unpaired chromatin. Analysis of gene expression in testes revealed that extra copy number alone was not sufficient for meiotic up-regulation of genes in the trisomic interval. Additionally and unexpectedly, presence of meiotic gene silencing chromatin modifications was not sufficient for down-regulation of genes in unpaired trisomic chromatin. Thus the meiotic chromatin modifications that are cytologically visible are unlikely to be directly involved in sterility versus fertility of DS models. Finally, the presence of an extra, unpaired chromosome, but not the presence of extra (trisomic) genes, caused global deregulation of transcription in spermatocytes. These results reveal mechanisms by which an extra chromosome, but not trisomic gene dose, impact on meiotic progress and infertility.
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