Dynamic changes in histone lysine lactylation during meiosis prophase I in mouse spermatogenesis

Male germ cells, which are responsible for producing millions of genetically diverse sperm through meiosis in the testis, rely on lactate as their central energy metabolite. Recent study has revealed that lactate induces epigenetic modification in cells through histone lysine lactylation. Here, we report dynamic histone lactylation at histone H4- lysine 5 (K5),- K8, and- K12 during meiosis prophase I in mouse spermatogenesis. By profiling the genome-wide occupancy of histone H4- K8 lactylation (H4K8la), which peaks at zygotene, our data show that H4K8la mark is observed at the promoters of genes exhibiting active expression with Gene Ontology functions enriched for meiosis. Notably, our data also demonstrate that H4K8la is closely associated with recombination hotspots, where machinery involved in the processing DNA double- stranded breaks, such as SPO11, DMC1, RAD51, and RPA2, is engaged. In addition, H4K8la was also detected at the meiosis- specific cohesion sites (marked by RAD21L and REC8) flanking the recombination hotspots. Functionally, our data show that lactate induces upregulation of key meiotic genes through H4K8la modifications. Additionally, H4K8la shows colocalization and interaction with PRDM9 at recombination hotspots. Finally, our data show that HBO1, a lactyltransferase, is highly expressed in meiotic germ cells. In vitro lactylation assays reveal that HBO1 induces H4K8la, and pharmacological inhibition of HBO1 in mice reduces H4K8la levels and disrupts meiosis. Collectively, our findings suggest that histone lactylation serves as an epigenetic mechanism that is involved in meiotic gene expression and recombination in male germ cells during spermatogenesis.