A novel CHD4-CTCF regulatory axis drives key developmental programs and transitions in male germ cells.

Sustained gamete production and testis development relies in developmental programs and transitions such as spermatogonia differentiation, meiosis, and spermiogenesis. Chromatin remodeling complexes and CTCF are key regulators of these processes by controlling specific patterns of gene expression across gamete development. Although the CHD4 chromatin remodeler and CTCF have been implicated in spermatogonia development, a mechanism explaining their cooperation is missing. We also do not know CHD4 and CTCF role in later stages of spermatogenesis. Our studies reveal that germ cell-specific deletion of CHD4 results in spermatogonia development defects and affects meiotic-specific functions such as homologous chromosome synapsis. Combined analysis of genome-wide chromatin binding and single cell gene transcription showed that CHD4 controls specific gene expression programs important for spermatogonia differentiation, transition into meiosis, and meiotic specific processes. Mechanistically, this can be explained by a pervasive role for CHD4 in controlling CTCF chromatin binding and transcriptional function. The discovery of a functional interplay between CHD4 and CTCF reveals a novel axis of gene expression control, integrating chromatin structure and transcriptional outcomes. This interaction is essential in orchestrating early testis development and meiotic processes, ensuring that the correct number of chromosomes is faithfully transmitted to the next generation.