Abstract
INTRODUCTION AND OBJECTIVES: Histone H4 acetylated at lysine K12 (H4K12ac) represents an activating epigenetic mark, which is present within sperm and prior to full decondensation of sperm chromatin during early embryogenesis. Together with silent sperm mRNAs, it may represent an epigenetic fingerprint monitoring past events of spermatogenesis with possible impact also on early embryo development. We therefore aimed to analyze whether association of H4K12ac with specific gene promoters is correlated with silent sperm mRNAs. Furthermore, the role of paternally derived H4K12ac for early embryo development should be clarified in the mouse model. METHODS: Sperm from fertile and subfertile men were subjected to ChIP-on-chip using anti-H4K12ac antibody. Data set was compared with genome-wide expression profiling of sperm mRNA. Functional studies comprized IVF in mice. RESULTS: In sperm from fertile men, H4K12ac-associated gene promoters expressed high levels of mRNAs. Many of these transcripts are coding testis-specific proteins, such as PHD finger protein 7 (PHF7) or testis development protein (NYD-SP6). Aberrant mRNA levels of these testis-specific genes were observed in subfertile patients. Immunofluorescence analysis of mouse preimplantation embryos revealed a strong signal for H4K12ac in the male pronuclus and a weaker signal in the female pronucleus. During pronuclei migration and at pronuclei fusion, an increasing H4K12ac signal could be observed in the female pronucleus, while the male pronucleus remained strongly labelled. CONCLUSIONS: Aberrant acetylation of H4K12ac within developmentally important gene promoters may reflect insufficient sperm chromatin compaction in subfertile men followed by inappropriate transfer of epigenetic information to the oocyte.
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