The Art of Packaging the Sperm Genome: Molecular and Structural Basis of the Histone-To-Protamine Exchange

Abstract

Male fertility throughout life hinges on the successful production of motile sperm, a developmental process that involves three coordinated transitions: mitosis, meiosis, and spermiogenesis. Germ cells undergo both mitosis and meiosis to generate haploid round spermatids, in which histones bound to the male genome are replaced with small nuclear proteins known as protamines. During this transformation, the chromatin undergoes extensive remodeling to become highly compacted in the sperm head. Despite its central role in spermiogenesis and fertility, we lack a comprehensive understanding of the molecular mechanisms underlying the remodeling process, including which remodelers/chaperones are involved, and whether intermediate chromatin proteins function as discrete steps, or unite simultaneously to drive successful exchange. Furthermore, it remains largely unknown whether more nuanced interactions instructed by protamine post-translational modifications affect chromatin dynamics or gene expression in the early embryo. Here, we bring together past and more recent work to explore these topics and suggest future studies that will elevate our understanding of the molecular basis of the histone-to-protamine exchange and the underlying etiology of idiopathic male infertility.

Keywords: chromatin remodeling; epigenetics; histone; histone displacement; sperm chromatin.

Figure 1

An overview of chromatin dynamics and intermediate stages of the histone-to-protamine exchange. Many histone variants are incorporated in meiotic spermatocytes, including H3.3, TH2A, and TH2B. Histone variant incorporation continues in post-meiotic round spermatids (H2AL2), concomitant with various histone PTMs that induce nucleosome destabilization. As spermatids begin elongation, TNPs and protamines are expressed and incorporated onto chromatin, but whether these act as discrete steps or co-occur remains unknown. It is also established that protamines acquire various PTMs, but the genomic localization of these PTMs (i.e. whether they occur randomly throughout the genome or localize into discrete domains) has not been determined. Ultimately, protamine-DNA binding forms toroidal structures of sperm chromatin, making sperm chromatin distinct from that of both oocytes and somatic cells. The contribution of sperm chromatin structure and the sperm epigenome to embryonic development will also be a fascinating area for future exploration. Cr,crotonylation; Ac, acetylation; Ub, ubiquitination; P, phosphorylation.