During spermatogenesis, the chromatin undergoes significant changes in architecture, with histones being largely replaced by protamines, inducing genome-wide condensation. Two papers provide insights into the regulators and mechanisms of this histone-to-protamine transition and its importance for male fertility.

On p. 3495, Leonard Guarente and colleagues analyse the consequences of SirT1 deletion in pre-meiotic spermatids. SirT1 is an NAD+-dependent deacetylase, the whole body deletion of which has been shown to impair male and female fertility via a systematic effect on reproductive hormone levels. However, whether it is also required in the germ cells themselves is not known. In this article, the authors show that SirT1 depletion specifically in the testis leads to a cell-autonomous defect in sperm maturation and male fertility. They find that histone hyperacetylation – one of the first steps in the chromatin changes of the histone-to-protamine transition – is significantly impaired, with consequent defects in the recruitment of downstream proteins required for histone removal and protamine deposition. Moreover, their data suggest that loss of SirT1 may accelerate reproductive ageing. Although the molecular mechanisms by which SirT1 regulates histone acetylation remain unclear, these data uncover an important role for this protein in the male germline.

Meanwhile, Paul Knoepfler and co-workers investigate the role of the histone H3 variant H3.3 in regulating spermatogenesis (p. 3483). H3.3 is generally associated with active transcription. Here, the authors generate a knockout of one of the two genes encoding H3.3, H3f3b, which leads to a strong reduction in H3.3 levels in the male germline. The mutant mice display a severe defect in sperm morphology and production, and hence in male fertility. Analysis of the chromatin state of H3f3b knockout germ cells reveals an increase in the levels of the repressive mark H3K9me3, and a decrease in H3K4 methylation, a mark of active chromatin. Importantly, the authors uncover defects in the histone-to-protamine transition, with both protamine levels and incorporation being reduced. These data provide the first insights into the role of H3.3 in mammalian spermatogenesis, and indicate an important role for this histone variant in regulating the striking changes in chromatin structure that accompany sperm formation.