A role for HDAC3 in regulating histone lactylation and maintaining oocyte chromatin architecture and fertility

ABSTRACT The establishment of specialized chromatin architecture is critical for oocyte development, meiotic fidelity, and embryogenesis. Histone lysine lactylation (Kla) has recently emerged as a widespread chromatin modification, yet its developmental dynamics and function in the germ line remain unclear. Here, we define the temporal profile of Kla during Drosophila oogenesis and identified enzymes that regulate its levels. Kla is absent in early germarial stages, becomes highly enriched during prophase I as meiotic chromosomes condense into the karyosome, and decreases when the karyosome decompacts during transcriptional reactivation. Germline depletion of HDAC3 and Nej/p300 reduces Kla in stage-10 oocytes, revealing conserved chromatin-modifying enzymes that maintain lactylation. Among these, HDAC3 is essential for sustaining karyosome architecture, assembling a normal meiotic spindle, and supporting fertility. These findings identify histone lactylation as a dynamic chromatin feature of oogenesis and suggest that Kla contributes to the establishment of meiotic chromatin states required for oocyte competence. SUMMARY STATEMENT Histone lactylation is developmentally regulated during Drosophila oogenesis. HDAC3 maintains histone lactylation and is essential for meiotic chromatin architecture, meiotic progression, and female fertility.