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.

Insights into the sperm chromatin and implications for male infertility from a protein perspective

“…This A-B and TADs compartmentalization correlates with retained histones in sperm. Some controversy arises from the use of current 3D-chromatin technologies in such compacted and inaccessible genome, which would potentially bias the results from the real in vivo genomic architecture (Moritz & Hammoud, 2022). Therefore, when globally evaluated, the results obtained so far lead to the hypothesis of a nonrandom dual behavior of the sperm nucleo-histone DNA, with a main enrichment of intergenic regions and repetitive DNA principally associated with centromeric loci, and the presence of promoters of developmental genes that would represent a minor proportion of the nucleosomal DNA (Castillo et al, 2015;Luense et al, 2019;Ozturk et al, 2021;Vavouri & Lehner, 2011;Yamaguchi et al, 2018; Figure 1).…”

“…This A‐B and TADs compartmentalization correlates with retained histones in sperm. Some controversy arises from the use of current 3D‐chromatin technologies in such compacted and inaccessible genome, which would potentially bias the results from the real in vivo genomic architecture (Moritz & Hammoud, 2022).…”

Nucleosomes in mammalian sperm: conveying paternal epigenetic inheritance or subject to reprogramming between generations?

“…In mammalian sperm, small basic proteins called protamines (PRMs) are the main constituents of chromatin. PRMs bind directly to DNA inducing circularization into toroidal structures ( Box 1 ) [1] . Nonetheless, early biochemical studies and revisited quantifications estimate residual histones in mature sperm as ~1–2% in mouse and ~4–10% in human compared with somatic genome equivalents 2 , 3 , 4 , 5 .…”

Global effects of identity and aging on the human sperm methylome

“…Sperm cells have unique epigenetic features not observed in somatic cells. Their chromatin is organized by protamines that significantly compact DNA in the sperm head [22]. The sperm methylome harbors additional HMRs at retrotransposons [23].…”