CCER1 condensates participate in histone-to-protamine transition by recruiting the TIP60/EPC1/NuA4 acetyltransferase...

Cases of idiopathic male infertility may be caused by as-yet unrecognized genetic factors. Here, we report that the testis-specific protein coiled-coil glutamate-rich protein 1 (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. We found that CCER1 nuclear aggregates may provide a 'reaction compartment' for the mutual recruitment of TIP60 and/or EPC1 subunits to the acetyltransferase NuA4 complex. Conversely, disruption of CCER1 droplets impairs the recruitment and interaction of TIP60 and 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.