Abstract

Cases of idiopathic male infertility may be caused by as-yet unrecognized genetic factors. Here, we report that the testis-specific protein CCER1 regulates male fertility through the formation of a dynamic membraneless organelle within the spermatid nucleus. Using a humanized CCER1 knock-in mouse line, we demonstrate that CCER1 function is conserved between mice and humans. Next, we generated Ccer1-Tag knock-in mice and analyzed CCER1-interacting proteins using immunoprecipitation-mass spectrometry (IP-MS). We found that CCER1 nuclear aggregates may provide a "reaction compartment" for the mutual recruitment of TIP60/EPC1 subunits to the acetyltransferase NuA4 complex. Conversely, disruption of CCER1 droplets impairs the recruitment and interaction of TIP60/EPC1 subunits, leading to reduced histone H4 hyperacetylation in nucleosomes, defective DNA strand breakage, and insufficient histone-to-protamine (HTP) replacement during spermiogenesis. In conclusion, our data indicate that the TIP60/EPC1/NuA4-CCER1 complex is involved in the epigenetic regulation of HTP replacement in the testis, providing new insights into the genetic and epigenetic etiology of male infertility.