Spermatogenesis Beyond DNA: Integrated RNA Control of the Epitranscriptome and Three-Dimensional Genome Architecture

Spermatogenesis is a tightly coordinated differentiation program that sustains male fertility while transmitting genetic and epigenetic information to the next generation. This review consolidates mechanistic evidence showing how RNA-centered regulation integrates with the epitranscriptome and three-dimensional (3D) genome architecture to orchestrate germ-cell fate transitions from spermatogonial stem cells through meiosis and spermiogenesis. Recent literature is critically surveyed and synthesized, with particular emphasis on human and primate data and on stage-resolved maps generated by single-cell and multi-omics technologies. Collectively, available studies support a layered regulatory model in which RNA-binding proteins and RNA modifications coordinate transcript processing, storage, translation, and decay; small and long noncoding RNAs shape post-transcriptional programs and transposon defense; and dynamic chromatin remodeling and 3D reconfiguration align transcriptional competence with recombination, sex-chromosome silencing, and genome packaging. Convergent nodes implicated in spermatogenic failure are highlighted, including defects in RNA metabolism, piRNA pathway integrity, epigenetic reprogramming, and nuclear architecture, and the potential of these frameworks to refine molecular phenotyping in male infertility is discussed. Finally, key gaps and priorities for causal testing in spatially informed, stage-specific experimental systems are outlined.