Defective imprint resetting in carriers of Robertsonian translocation Rb (8.12) Aabida Saferali • Soizik Berlivet • John Schimenti • Marisa S. Bartolomei • Teruko Taketo • Anna K. Naumova Received: 22 March 2010 / Accepted: 3 June 2010 / Published online: 25 June 2010 Ó Springer Science+Business Media, LLC 2010 Abstract Meiotic silencing of unsynapsed chromatin (MSUC) occurs in the germ cells of translocation carriers and may cause meiotic arrest and infertility. We hypothe- sized that if bypassing meiotic checkpoints MSUC may cause epigenetic defects in sperm. We investigated the meiotic behavior of the Robertsonian translocation Rb (8.12) in mice. The unsynapsed 8 and 12 trivalent was associated with the XY body during early and mid-pach- ynema in heterozygous Rb (8.12) carriers, suggesting possible silencing of pericentromeric genes, such as the Dnmt3a gene. In wild-type mice, DNMT3A protein showed a dramatic accumulation in the nucleus during the mid-pachytene stage and distinct association with the XY body. In translocation carriers, DNMT3A was less abun- dant in a proportion of pachytene spermatocytes that also had unsynapsed pericentromeric regions of chromosomes 8 and 12. The same mice had incomplete methylation of the imprinted H19 differentially methylated region (DMR) in sperm. We propose that impaired H19 imprint establish- ment results from lack of synapsis in chromosomes 8 and 12 probably through transient silencing of a chromosome 8 or 12 gene during pachynema. Furthermore, our findings support the notion that imprint establishment at the H19 locus extends into pachynema. Introduction Meiotic silencing of unsynapsed chromatin (MSUC) is a normal process that takes place during the pachytene stage of male meiosis in mammals and results in silencing of most of the X and Y genes. MSUC is also detected in carriers of chromosomal translocations in humans and mice and often leads to the activation of mid-pachytene check- point response and hence spermatogenic arrest and reduced fertility (Homolka et al. 2007; Mahadevaiah et al. 2008). The exact mechanism of the pachytene checkpoint acti- vation remains a subject of debate (Burgoyne et al. 2009) and several hypotheses have been proposed, including Electronic supplementary material The online version of this article (doi:10.1007/s00335-010-9271-9) contains supplementary material, which is available to authorized users. A. Saferali Á A. K. Naumova Department of Human Genetics, McGill University, Montreal, QC, Canada S. Berlivet Á T. Taketo Á A. K. Naumova Department of Obstetrics and Gynecology, Faculty of Medicine, McGill University, Montreal, QC, Canada J. Schimenti Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA M. S. Bartolomei Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, 415 Curie Blvd, Philadelphia, PA 19104-6148, USA T. Taketo Department of Surgery, Faculty of Medicine, McGill University, Montreal, QC, Canada T. Taketo Á A. K. Naumova The Research Institute of the McGill University Health Centre, Montreal, QC, Canada A. K. Naumova (&) Department of Obstetrics and Gynecology, Royal Victoria Hospital, F3.32, 687 Pine Ave. West, Montreal, QC H3A 1A1, Canada e-mail: anna.naoumova@mcgill.ca 123 Mamm Genome (2010) 21:377–387 DOI 10.1007/s00335-010-9271-9