LSD1 exerts crucial functions to drive the progression of meiotic prophase I during spermatogenesis.

Epigenetic modifications are critical determinants governing the proper initiation and progression of gametogenesis. Accumulating evidence has indicated that epigenetic dysregulation underlies the pathogenesis of infertility. However, detailed information on the individual powerful roles of these epigenetic enzymes in facilitating programmed meiosis remains elusive. This study indicates that lysine-specific demethylase 1 (LSD1) plays critical roles during meiotic prophase I in mouse spermatogenesis. Germ cell-specific deletion of the Lsd1 gene in male mice caused meiotic arrest at the pachytene stage, ultimately leading to infertility. In primary spermatocytes of Lsd1-deficient mice, compromised homologous chromosome synapsis and DNA double-strand break repair activated the DNA damage checkpoint pathway, triggering spermatocyte apoptosis. Mechanistically, LSD1 directly binds to the promoters of meiotic genes, including Prdm9 and Rpa2, to regulate their expression during meiosis. PRDM9 and RPA2 are upregulated upon LSD1 loss and are essential for homologous recombination and DNA double-strand break repair. The promoters of Prdm9 and Rpa2 are also occupied by H3K4me2, whose levels increase upon LSD1 loss. Collectively, this study highlights the crucial role of LSD1 in orchestrating meiotic genes, possibly through its demethylase activity during spermatogenesis, and may help explain the pathology of non-obstructive azoospermia in humans.