Abstract
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.
Highlights
During mammalian male meiosis, the heteromorphic sex chromosomes (X and Y) condense in a separate chromatin domain known as the XY or sex body
We examined primary spermatogenic cell samples of 3 patients and 3 controls which were obtained from testicular biopsies
The nuclear localization of the XY body was determined for all pachytene spermatocytes analyzed in Table 1 to investigate if there is a relation between nuclear localization and H3.1/3.2 nucleosome eviction
Summary
The heteromorphic sex chromosomes (X and Y) condense in a separate chromatin domain known as the XY or sex body (reviewed in [1]). XY body formation starts at the zygotene to pachytene transition of prophase I [1] and persisting DNA double strand breaks (DSBs), made by SPO11 at the onset of meiosis, contribute to its formation [2]. Autosomal chromosomes are able to repair these breaks by searching for their homolog, subsequently forming a so-called bivalent in which paternally and maternally derived chromatids are closely aligned, intermediated by the synaptonemal complex (SC). The X and Y chromosomes are largely heterologous and show homologous synapsis only at the small pseudoautosomal region (PAR). Non-synapsis of chromosomal axial elements is detected by BRCA1 which localises ATR, a member of the PI3-like kinase family, to the X,Y chromosomes, followed by phosphorylation of H2AX at serine 139 [3]. From its formation on, the XY body is positive for cH2AX [4]
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