The X and Y chromosome in meiosis: how and why they keep silent

Abstract

T he XX/XY sex chromosomal system of mammals, including human, challenges the chromosome pairing mechanism during male meiosis. Pairing and subsequent separation of homologous chromosomes generates haploid cells from diploid cells during the meiotic divisions. One of the basic requirements for recognition between homologous chromosomes is DNA sequence identity. Since the X and Y chromosome share little homology, their quest for each other is difficult, and has special characteristics. During the lengthy meiotic prophase, all autosomal chromosomes synapse, by forming a special protein structure called the synaptonemal complex, which connects the chromosomal axes. In contrast, the X and Y chromosome synapse only in the short homologous pseudoautosomal regions, and form the so-called XY body. 1 In this specialized chromatin area, transcription is shut down by a mechanism named meiotic sex chromosome inactivation (MSCI) (reviewed by Refs. 2 and 3). The sex chromosomes remain silent throughout the rest of meiotic prophase, and only few sexlinked genes are (re)activated in postmeiotic spermatids. 2 Since long, scientists have wondered how MSCI is achieved, and what its biological significance is.Recently, two papers 4,5 significantly increased our understanding of how and why MSCI works.So far, the only molecule that was known to be absolutely essential for initiation of MSCI was cH2AX. 6 This phosphorylated form of histone H2AX marks the XY body from its formation until diplotene in mouse. 7 In mice lacking H2AX, no XY body is formed, the sex chromosomes are not silenced and meiosis arrests at pachytene. 6 The phosphorylation of H2AX at the XY body is mediated by the checkpoint kinase ATR that can be visualized along the unsynapsed axes of X and Y from late zygotene onwards. 8 In their recent paper, Ichijima et al. 4 reveal that the phosphorylation of H2AX occurs in two phases; first, it is restricted to the chromosomal axes, then the area extends, and H2AX also becomes phosphorylated in the surrounding chromatin loops. This second phase, when cH2AX spreads, depends on a protein named mediator of DNA damage checkpoint 1 (MDC1), and this function is required for transcriptional silencing of the sex chromosomes ( Figure 1). MDC1 is a known binding partner of cH2AX, 9,10 and both proteins, as well as ATR, are well known for their role in the DNA damage response pathway in somatic cells. This pathway plays a pivotal role in sensing the presence of single-stranded DNA at stalled replication forks to allow repair as well as activation of cell cycle checkpoints. Interestingly, the authors also analyzed the role of MDC1 in somatic cells. In analogy to their observations in meiotic cells, they observed reduced amplification of ATRdependent cH2AX signals after replicative stress in the absence of MDC1, compared to control cells. They also showed that RNA polymerase II is excluded from chromatin at replication-stalled sites that are marked by ATR-and MDC1-dependent cH2AX accumulation, thereby confirming and extending the obser...

Epigenetics drive the evolution of sex chromosomes in animals and plants

“…During meiosis in eutherians and marsupials, the X and Y chromosomes undergo meiotic sex chromosome inactivation (MSCI), in which most sex-linked genes are inactivated [104][105][106][107][108]. This process is mediated by epigenetic modifications, through chromatin condensation and heterochromatin formation, and the X and Y chromosomes are packaged into a compact structure, called the sex body [104][105][106][107][108]. MSCI is initiated at meiotic prophase I and is retained during late spermatogenesis, repressing most sex-linked genes during sperm differentiation.…”

New transcriptomic tools to understand testis development and functions

“…The authors also confirmed that the transcription of some spermiogenesis-related genes is initiated as early as pachytene Spc. They also found that some Xlinked genes are overexpressed during meiosis, thus escaping the meiotic sex chromosome inactivation (MSCI) (Ichijima et al, 2012;van der Heijden et al, 2011). Another RNA-seq study on five enriched mouse GCs populations focused on lncRNAs and also identified candidate genes that escape MSCI (Wichman et al, 2017).…”

Functional significance of the sex chromosomes during spermatogenesis

“…1). Unlike autosomes that undergo synapsis along their entire lengths during meiosis, large regions of the X and Y chromosomes remain unsynapsed and trigger transcriptional silencing, called meiotic sex chromosome inactivation (MSCI: reviewed elsewhere (Ichijima, et al 2012, Turner 2007, van der Heijden, et al 2011)). MSCI is accompanied by the formation of distinct heterochromatin called the XY body (also known as the sex body).…”