Reinholdt Laura G, Czechanski Anne, Kamdar Sonya, King Benjamin L, Sun Fengyun, Handel Mary Ann
The Jackson Laboratory, Bar Harbor, ME 04609, USA.
Chromosoma. 2009 Dec;118(6):723-36. doi: 10.1007/s00412-009-0230-8. Epub 2009 Jul 29.
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 upregulation of genes in the trisomic interval. Additionally and unexpectedly, presence of meiotic gene silencing chromatin modifications was not sufficient for downregulation 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.
非整倍体在减数分裂过程中会导致染色体轴不成对，常伴有不育症。我们之前使用三种唐氏综合征小鼠模型表明，与雄性不育及减数分裂后生殖细胞几乎缺失相关的是额外的染色体，而非额外的基因剂量。在此，我们检验这样一个假说：非整倍体片段在减数分裂过程中会根据其是否作为额外染色体存在而发生不同的修饰和表达。在所有检测的三种模型中，三体区域都缺乏配对伙伴，但在一种情况下，精母细胞有一条额外的（且不成对的）染色体，而另外两种模型涉及三体区域的易位而非额外染色体。一条额外的不成对染色体会一直被组蛋白H2AX磷酸化修饰，且缺乏RNA聚合酶II。但在三体区域与配对染色体相连的情况下，这些蛋白质修饰的组装会受到三体区域相对于着丝粒的位置以及未配对染色质物理范围的影响。对睾丸中基因表达的分析表明，仅额外的拷贝数不足以使三体区间内的基因在减数分裂时上调。此外且出乎意料的是，减数分裂基因沉默染色质修饰的存在不足以使未配对三体染色质中的基因下调。因此，在细胞学上可见的减数分裂染色质修饰不太可能直接参与唐氏综合征模型的不育与可育情况。最后，额外不成对染色体的存在，而非额外（三体）基因的存在，导致了精母细胞转录的全局失调。这些结果揭示了额外染色体而非三体基因剂量影响减数分裂进程和不育症的机制。
