Protamines: lessons learned from mouse models

Abstract

The packaging and safeguarding of paternal DNA in the sperm cell nucleus is a critical feature of proper sperm function. Histones cannot mediate the necessary hypercondensation and shielding of chromatin required for motility and transit through the reproductive tracts. Paternal chromatin is therefore reorganized and ultimately packaged by protamines. In most mammalian species one protamine is present in mature sperm (PRM1). In rodents and primates among others, however, mature sperm contain a second protamine (PRM2). Unlike PRM1, PRM2 is cleaved at its N-terminal end. Although protamines have been studied for decades due to their role in chromatin hypercondensation and involvement in male infertility key aspects of their function are still unclear. This review updates and integrates our knowledge of protamines and their function based on lessons learned from mouse models and starts to answer open questions. The combined insights from recent work reveal that indeed both protamines are crucial for the production of functional sperm and indicate that the two protamines perform distinct functions beyond simple DNA compaction. Loss of one allele of PRM1 leads to subfertility whereas heterozygous loss of PRM2 does not. Unprocessed PRM2 seems to play a distinct role related to the eviction of intermediate DNA bound proteins and the incorporation of both protamines into chromatin. For PRM1, on the other hand, heterozygous loss leads to strongly reduced sperm motility as the main phenotype, indicating that PRM1 might be important for processes ensuring correct motility, apart from DNA compaction.

Histone removal in sperm protects paternal chromosomes from premature division at fertilization

“…Incidentally, this study also establishes that histone elimination during Drosophila spermiogenesis is a sequential process, with the removal of H2A-H2B and H3-H4 being temporally and functionally distinct. Notably, during mouse spermiogenesis, the replacement of H2A and H2B with testis-specific histone variants prepares the final replacement of nucleosomes with protamines ( 42 – 44 ), whereas in Xenopus , only H2A-H2B dimers are partially replaced with SNBPs, leading to the retention of H3 and H4 in sperm ( 45 ). The sequential elimination of histones in spermatids could thus be widespread in animals.…”

“…The recurrent packaging of sperm DNA with nonhistone proteins is a longstanding mystery in chromatin biology and evolution. Main hypotheses on this specialization include sperm nuclear compaction, transcriptional shutdown in spermatids, and sperm DNA protection against damages ( 5 , 44 , 46 ). Our work now suggests that the timing of egg fertilization with respect to female meiosis progression is a previously unexplored, key determinant of sperm chromatin evolution in animals.…”

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

“…The replacement of histones by protamines initiates in early elongating spermatids upon translation of transition proteins (TNPs) and PRMs ( Box 1 ) ( Figure 1 ). While TNP1 and TNP2 are not required for histone eviction, they are necessary for proper sperm chromatin condensation, PRM2 proteolytic cleavage, and proficient fertility 1 , 7 . PRM1 and PRM2 are instead essential and nonredundant for histone displacement, as well as for sperm chromatin compaction, DNA integrity, and male fertility in mice and humans 1 , 7 .…”

“…While TNP1 and TNP2 are not required for histone eviction, they are necessary for proper sperm chromatin condensation, PRM2 proteolytic cleavage, and proficient fertility 1 , 7 . PRM1 and PRM2 are instead essential and nonredundant for histone displacement, as well as for sperm chromatin compaction, DNA integrity, and male fertility in mice and humans 1 , 7 . Before histone eviction, numerous testis-specific histone variants load onto chromatin and multiple histone PTMs become upregulated in early elongating spermatids.…”

“…Nuclear compaction co-occurs with extensive displacement of histones from the genome and incorporation of protamines following an apical–caudal directionality. Whereas all mammals express PRM1, primates, most rodents, and some other placental mammals also express PRM2 [7] . PRM2 is translated as a precursor and matures through proteolytic cleavage of its N-terminal sequence.…”