DNA methylome of primary spermatocyte reveals epigenetic dysregulation associated with male sterility of cattleyak

DNA cytosine methylation modification in the germline is of particular importance since it is a highly heritable epigenetic mark. Although cytosine methylation has been analyzed at the genome-scale for several mammalian species, our knowledge of DNA methylation patterns and the mechanisms underlying male hybrid sterility is still limited in domestic animals such as cattleyak. Here we for the first time show the genome-wide and single-base resolution landscape of methylcytosines (mC) in the primary spermatocyte (PSC) genome of yak with normal spermatogenesis and the inter-specific hybrid cattleyak with male infertility. A comparative investigation revealed that widespread differences are observed in the composition and patterning of DNA cytosine methylation between the two methylomes. Global CG or non-CG DNA methylation levels, as well as the number of mC sites, are increased in cattleyak compared to yak. Notably, the DNA methylome in cattleyak PSC exhibits promoter hypermethylation of meiosis-specific genes and piRNA pathway genes with respect to yak. Furthermore, major retrotransposonson classes are predominantly hypermethylated in cattleyak while those are fully hypomethylated in yak. KEGG pathway enrichment indicates Rap1 signaling and MAPK pathways may play potential roles in the spermatogenic arrest of cattleyak. Our present study not only provides valuable insights into distinct features of the cattleyak PSC methylome but also paves the way toward elucidating the complex, yet highly coordinated epigenetic modification during male germline development for inter-specific hybrid animals.