Department of Obstetrics and Gynaecology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
PLoS One. 2012;7(2):e31485. doi: 10.1371/journal.pone.0031485. Epub 2012 Feb 15.
In mammalian male gametogenesis the sex chromosomes are distinctive in both gene activity and epigenetic strategy. At first meiotic prophase the heteromorphic X and Y chromosomes are placed in a separate chromatin domain called the XY body. In this process, X,Y chromatin becomes highly phosphorylated at S139 of H2AX leading to the repression of gonosomal genes, a process known as meiotic sex chromosome inactivation (MSCI), which has been studied best in mice. Post-meiotically this repression is largely maintained. Disturbance of MSCI in mice leads to harmful X,Y gene expression, eventuating in spermatocyte death and sperm heterogeneity. Sperm heterogeneity is a characteristic of the human male. For this reason we were interested in the efficiency of MSCI in human primary spermatocytes. We investigated MSCI in pachytene spermatocytes of seven probands: four infertile men and three fertile controls, using direct and indirect in situ methods. A considerable degree of variation in the degree of MSCI was detected, both between and within probands. Moreover, in post-meiotic stages this variation was observed as well, indicating survival of spermatocytes with incompletely inactivated sex chromosomes. Furthermore, we investigated the presence of H3K9me3 posttranslational modifications on the X and Y chromatin. Contrary to constitutive centromeric heterochromatin, this heterochromatin marker did not specifically accumulate on the XY body, with the exception of the heterochromatic part of the Y chromosome. This may reflect the lower degree of MSCI in man compared to mouse. These results point at relaxation of MSCI, which can be explained by genetic changes in sex chromosome composition during evolution and candidates as a mechanism behind human sperm heterogeneity.
在哺乳动物雄性配子发生过程中，性染色体在基因活性和表观遗传策略上都有独特的表现。在第一次减数分裂前期，异型的 X 和 Y 染色体被放置在一个称为 XY 体的单独染色质域中。在这个过程中，X、Y 染色质在 H2AX 的 S139 处高度磷酸化，导致性腺基因的抑制，这个过程被称为减数分裂性染色体失活（MSCI），在小鼠中研究得最为深入。减数分裂后，这种抑制在很大程度上得到维持。在小鼠中 MSCI 的干扰会导致有害的 X、Y 基因表达，最终导致精母细胞死亡和精子异质性。精子异质性是人类男性的一个特征。出于这个原因，我们对人类初级精母细胞中 MSCI 的效率感兴趣。我们使用直接和间接原位方法研究了七个供体的粗线期精母细胞中的 MSCI：四个不育男性和三个正常生育对照。我们检测到 MSCI 的程度在供体之间和供体内部都存在相当大的差异。此外，在减数分裂后阶段也观察到了这种差异，表明存在不完全失活的性染色体的精母细胞存活。此外，我们还研究了 X 和 Y 染色质上 H3K9me3 后翻译修饰的存在。与组成性着丝粒异染色质相反，这种异染色质标记物并没有特异性地积累在 XY 体上，除了 Y 染色体的异染色质部分。这可能反映了人类 MSCI 程度低于小鼠。这些结果表明 MSCI 松弛，这可以通过性染色体组成在进化过程中的遗传变化来解释，并且是人类精子异质性背后的机制之一。
