Pachytene asynapsis drives meiotic sex chromosome inactivation and leads to substantial postmeiotic repression in spermatids.

Transcriptional silencing of the sex chromosomes during male meiosis (MSCI) is conserved among organisms with limited sex chromosome synapsis, including mammals. Since the 1990s the prevailing view has been that MSCI in mammals is transient, with sex chromosome reactivation occurring as cells exit meiosis. Recently, we found that any chromosome region unsynapsed during pachytene of male and female mouse meiosis is subject to transcriptional silencing (MSUC), and we hypothesized that MSCI is an inevitable consequence of this more general meiotic silencing mechanism. Here, we provide direct evidence that asynapsis does indeed drive MSCI. We also show that a substantial degree of transcriptional repression of the sex chromosomes is retained postmeiotically, and we provide evidence that this postmeiotic repression is a downstream consequence of MSCI/MSUC. While this postmeiotic repression occurs after the loss of MSUC-related proteins at the end of prophase, other histone modifications associated with transcriptional repression have by then become established.

[1]  R. Metzenberg,et al.  Meiotic Silencing by Unpaired DNA , 2001, Cell.

[2]  K. Manova,et al.  H2AX is required for chromatin remodeling and inactivation of sex chromosomes in male mouse meiosis. , 2003, Developmental cell.

[3]  Jeannie T. Lee,et al.  X-chromosome inactivation: a hypothesis linking ontogeny and phylogeny , 2005, Nature Reviews Genetics.

[4]  J. Grootegoed,et al.  Specific aspects of the ubiquitin system in spermatogenesis , 2000, Journal of endocrinological investigation.

[5]  S. Mahadevaiah,et al.  XYY spermatogenesis in XO/XY/XYY mosaic mice. , 1990, Cytogenetics and cell genetics.

[6]  Jeannie T. Lee,et al.  Inheritance of a pre-inactivated paternal X chromosome in early mouse embryos , 2003, Nature.

[7]  S. Ohno,et al.  Cytological study of an X-autosome translocation in Mus musculus. , 1962, Cytogenetics.

[8]  W. Reik,et al.  Developmental biology: The X-inactivation yo-yo , 2005, Nature.

[9]  P. Hendriksen,et al.  Do X and Y spermatozoa differ in proteins? , 1999, Theriogenology.

[10]  Ahmad M Khalil,et al.  Dynamic histone modifications mark sex chromosome inactivation and reactivation during mammalian spermatogenesis. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[11]  Mary Ann Handel,et al.  The XY body: a specialized meiotic chromatin domain. , 2004, Experimental cell research.

[12]  J. Schimenti,et al.  Synapsis or silence , 2005, Nature Genetics.

[13]  A. Solari.  The behaviour of chromosomal axes in Searle's X-autosome translocation , 2004, Chromosoma.

[14]  A. Ashworth,et al.  A zinc finger protein-encoding gene expressed in the post-meiotic phase of spermatogenesis. , 1991, Gene.

[15]  J. Hoeijmakers,et al.  Histone ubiquitination and chromatin remodeling in mouse spermatogenesis. , 1999, Developmental biology.

[16]  C. Disteche,et al.  Evidence for de novo imprinted X-chromosome inactivation independent of meiotic inactivation in mice , 2005, Nature.

[17]  P. Park,et al.  Postmeiotic Sex Chromatin in the Male Germline of Mice , 2006, Current Biology.

[18]  B. Oostra,et al.  Postmeiotic transcription of X and Y chromosomal genes during spermatogenesis in the mouse. , 1995, Developmental biology.

[19]  T. Katada,et al.  cDNA cloning of mouse BLM gene, the homologue to human Bloom's syndrome gene, which is highly expressed in the testis at the mRNA level. , 1998, Biochimica et biophysica acta.

[20]  W. G. Kelly,et al.  Meiotic pairing and imprinted X chromatin assembly in Caenorhabditis elegans , 2004, Nature Genetics.

[21]  J. Hoeijmakers,et al.  Silencing of Unpaired Chromatin and Histone H2A Ubiquitination in Mammalian Meiosis , 2005, Molecular and Cellular Biology.

[22]  G. Roeder,et al.  The pachytene checkpoint. , 2000, Trends in genetics : TIG.

[23]  C. Deng,et al.  BRCA1, Histone H2AX Phosphorylation, and Male Meiotic Sex Chromosome Inactivation , 2004, Current Biology.

[24]  A. Solari,et al.  The prevalence of a YY synaptonemal complex over XY synapsis in an XYY man with exclusive XYY spermatocytes , 1997, Chromosome Research.

[25]  D. Reinberg,et al.  Epigenetic Dynamics of Imprinted X Inactivation During Early Mouse Development , 2004, Science.

[26]  L. Carrel,et al.  Germ cell development in the XXY mouse: evidence that X chromosome reactivation is independent of sexual differentiation. , 1999, Developmental biology.

[27]  S. Mahadevaiah,et al.  An analysis of meiotic impairment and of sex chromosome associations throughout meiosis in XYY mice , 2000, Cytogenetic and Genome Research.

[28]  R. Camerini-Otero,et al.  SPO11 is required for sex-body formation, and Spo11 heterozygosity rescues the prophase arrest of Atm-/- spermatocytes , 2005, Journal of Cell Science.

[29]  K. Loveland,et al.  Deletions on mouse Yq lead to upregulation of multiple X- and Y-linked transcripts in spermatids. , 2005, Human molecular genetics.

[30]  C. Heyting,et al.  The gene encoding a major component of the lateral elements of synaptonemal complexes of the rat is related to X-linked lymphocyte-regulated genes , 1994, Molecular and cellular biology.

[31]  A. Solari.  The behavior of the XY pair in mammals. , 1974, International review of cytology.

[32]  R. Lovell-Badge,et al.  Mouse homologues of the human AZF candidate gene RBM are expressed in spermatogonia and spermatids, and map to a Y chromosome deletion interval associated with a high incidence of sperm abnormalities. , 1998, Human molecular genetics.

[33]  S. Keeney,et al.  Recombinational DNA double-strand breaks in mice precede synapsis , 2001, Nature Genetics.

[34]  S. Tilghman,et al.  Optimizing the detection of nascent transcripts by RNA fluorescence in situ hybridization. , 2001, Nucleic acids research.

[35]  Cameron S. Osborne,et al.  Active genes dynamically colocalize to shared sites of ongoing transcription , 2004, Nature Genetics.

[36]  A. Solari,et al.  The histology and cytology of the seminiferous epithelium of mice carrying Searle's X-autosome translocation. , 1969, Acta physiologica latino americana.

[37]  P. Burgoyne,et al.  Genetic homology and crossing over in the X and Y chromosomes of mammals , 2004, Human Genetics.

[38]  J. McCarrey,et al.  Transcriptional analysis of the candidate spermatogenesis gene Ube1y and of the closely related Ube1x shows that they are coexpressed in spermatogonia and spermatids but are repressed in pachytene spermatocytes. , 1996, Developmental biology.

[39]  T. Rodríguez,et al.  Evidence that sex chromosome asynapsis, rather than excess Y gene dosage, is responsible for the meiotic impairment of XYY mice , 2000, Cytogenetic and Genome Research.

[40]  C. E. Ford,et al.  A RECIPROCAL TRANSLOCATION IN THE MOUSE BETWEEN THE X CHROMOSOME AND A SHORT AUTOSOME. , 1964, Cytogenetics.

[41]  K. Loveland,et al.  Identification of novel Y chromosome encoded transcripts by testis transcriptome analysis of mice with deletions of the Y chromosome long arm , 2005, Genome Biology.

[42]  A. Clarke,et al.  The meiotic checkpoint monitoring sypapsis eliminates spermatocytes via p53-independent apoptosis , 1998, Nature Genetics.

[43]  L. Hurst.  Is Stellate a relict meiotic driver? , 1992, Genetics.