Argonaute proteins regulate the timing of the spermatogenic transcriptional program [RNA-seq]

Using a triple Ago413-/- mouse model, we show that AGO3 and AGO4 are key regulators of spermatogenesis, orchestrating expression of meiosis-related genes during prophase I, while maintaining silencing of spermiogenesis genes. Overexpression of spermiogenesis genes during prophase I in Ago413-/- mice results in subfertility.

Here, we show that AGO3, but not AGO2, localizes to the sex chromatin of pachytene spermatocytes, where together with AGO4, it is required for transcriptional silencing of XY-linked genes. We also identify BRG1, a BAF complex subunit as an AGO3 interactor, and observe that loss of AGO3 and AGO4 leads to increased BRG1 in spermatocytes, evidencing a role for AGO3 in transcriptional control during meiosis. Notably, we reveal that altered gene regulation during prophase I given by loss of AGO3 and AGO4 transcends the meiotic phase of spermatogenesis, leading to poor quality germ cells.