Meiotic sex chromosome inactivation and the XY body: a phase separation hypothesis

In mammals, the X and Y chromosomes share only small regions of homology called pseudo-autosomal regions (PAR) where pairing and recombination in spermatocytes can occur. Consequently, the sex chromosomes remain largely unsynapsed during meiosis I and are sequestered in a nuclear compartment known as the XY body where they are transcriptionally silenced in a process called meiotic sex chromosome inactivation (MSCI). MSCI mirrors meiotic silencing of unpaired chromatin (MSUC), the sequestration and transcriptional repression of unpaired DNA observed widely in eukaryotes. MSCI is initiated by the assembly of the axial elements of the synaptonemal complex (SC) comprising the structural proteins SYCP2 and SYCP3 followed by the ordered recruitment of DNA Damage Response (DDR) factors to effect gene silencing. However, the precise mechanism of how unsynapsed chromatin is detected in meiocytes is poorly understood. The sex chromosomes in eutherian mammals harbor multiple clusters of SYCP3-like amplicons comprising the Xlr gene family, only a handful of which have been functionally studied. We used a shRNA-transgenic mouse model to create a deficiency in the testis-expressed multicopy Xlr3 genes to investigate their role in spermatogenesis. Here we show that knockdown of Xlr3 in mice leads to spermatogenic defects and a skewed sex ratio that can be traced to MSCI breakdown. Spermatocytes deficient in XLR3 form the XY body and the SC axial elements therein, but are compromised in their ability to recruit DDR components to the XY body.

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A Hypothesis: Linking Phase Separation to Meiotic Sex Chromosome Inactivation and Sex-Body Formation

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.674203 ◽

2021 ◽

Vol 9 ◽

Author(s):

Yiding Xu ◽

Huanyu Qiao

Keyword(s):

Phase Separation ◽

Sex Chromosomes ◽

Sex Chromosome ◽

Chromosome Inactivation ◽

Pseudoautosomal Region ◽

Future Research ◽

Homologous Region ◽

Body Formation ◽

Meiotic Sex Chromosome Inactivation ◽

Sex Chromosome Inactivation

During meiotic prophase I, X and Y chromosomes in mammalian spermatocytes only stably pair at a small homologous region called the pseudoautosomal region (PAR). However, the rest of the sex chromosomes remain largely unsynapsed. The extensive asynapsis triggers transcriptional silencing - meiotic sex chromosome inactivation (MSCI). Along with MSCI, a special nuclear territory, sex body or XY body, forms. In the early steps of MSCI, DNA damage response (DDR) factors, such as BRCA1, ATR, and γH2AX, function as sensors and effectors of the silencing signals. Downstream canonical repressive histone modifications, including methylation, acetylation, ubiquitylation, and SUMOylation, are responsible for the transcriptional repression of the sex chromosomes. Nevertheless, mechanisms of the sex-body formation remain unclear. Liquid-liquid phase separation (LLPS) may drive the formation of several chromatin subcompartments, such as pericentric heterochromatin, nucleoli, inactive X chromosomes. Although several proteins involved in phase separation are found in the sex bodies, when and whether these proteins exert functions in the sex-body formation and MSCI is still unknown. Here, we reviewed recent publications on the mechanisms of MSCI and LLPS, pointed out the potential link between LLPS and the formation of sex bodies, and discussed its implications for future research.

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