Loss of <i>Prm1</i> leads to defective chromatin protamination, impaired PRM2 processing, reduced sperm motility and subfertility in male mice

Merges, Gina Esther; Meier, Julia; Schneider, Simon; Kruse, Alexander; Fröbius, Andreas C.; Kirfel, Gregor; Steger, Klaus; Arévalo, Lena; Schorle, Hubert

doi:10.1242/dev.200330

Cited by 27 publications

(36 citation statements)

References 66 publications

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“…Of note, a recent study investigating a single residue mutation in PRM1 showed increased histone retention, but no disturbances in transition protein retention in such mice [ 46 ]. In Prm1 -/- transition protein retention is also present, albeit weaker than seen here [ 38 ]. Transition proteins are believed to aid in chromatin condensation by stabilizing the DNA in a non-supercoiled state, cooperating with topoisomerases to relieve torsional stress and to be involved in DNA repair during chromatin condensation [ 53 – 55 ].…”

Section: Discussionmentioning

confidence: 47%

“…While in WT condensed spermatids unprocessed PRM2 seems to accumulate in cytoplasm and residual bodies in Prm2 +/Δc mice it is detected in the nucleus and does not seem to be evicted into the cytoplasm. Incomplete PRM2 processing has been reported in several mouse models of genes involved in the histone-to-protamine transition, such as transition proteins, PRM1 and H2A.L.2 [ 8 , 21 , 23 , 38 , 46 , 52 ]. At least in this study, however, it seems that rather than failure of complete processing of PRM2 we see a failure of eviction of unprocessed PRM2 into the cytoplasm.…”

Section: Discussionmentioning

confidence: 99%

“…The membranes were then washed and incubated with an HRP-labelled secondary antibody followed by chemiluminescent detection using Westar NOVA 2.0 chemiluminescent substrate (Cyanagen, Bologna, Italy) or SuperSignal West Femto Maximum Sensitivity Substrate (Thermo Fisher Scientific, Waltham, USA). Since Merges et al [ 38 ] was able to show that (outer dense fiber protein 2) ODF2, which is a major component of the sperm tail, is compatible with AU-PAGE and represents one of the prominent bands in the upper part of the Coomassie AU gel we used the protein as a loading control.…”

Section: Methodsmentioning

confidence: 99%

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Loss of the cleaved-protamine 2 domain leads to incomplete histone-to-protamine exchange and infertility in mice

et al. 2022

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Protamines are unique sperm-specific proteins that package and protect paternal chromatin until fertilization. A subset of mammalian species expresses two protamines (PRM1 and PRM2), while in others PRM1 is sufficient for sperm chromatin packaging. Alterations of the species-specific ratio between PRM1 and PRM2 are associated with infertility. Unlike PRM1, PRM2 is generated as a precursor protein consisting of a highly conserved N-terminal domain, termed cleaved PRM2 (cP2), which is consecutively trimmed off during chromatin condensation. The carboxyterminal part, called mature PRM2 (mP2), interacts with DNA and together with PRM1, mediates chromatin-hypercondensation. The removal of the cP2 domain is believed to be imperative for proper chromatin condensation, yet, the role of cP2 is not yet understood. We generated mice lacking the cP2 domain while the mP2 is still expressed. We show that the cP2 domain is indispensable for complete sperm chromatin protamination and male mouse fertility. cP2 deficient sperm show incomplete protamine incorporation and a severely altered protamine ratio, retention of transition proteins and aberrant retention of the testis specific histone variant H2A.L.2. During epididymal transit, cP2 deficient sperm seem to undergo ROS mediated degradation leading to complete DNA fragmentation. The cP2 domain therefore seems to be a key aspect in the complex crosstalk between histones, transition proteins and protamines during sperm chromatin condensation. Overall, we present the first step towards understanding the role of the cP2 domain in paternal chromatin packaging and open up avenues for further research.

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Section: Discussionmentioning

confidence: 47%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Loss of the cleaved-protamine 2 domain leads to incomplete histone-to-protamine exchange and infertility in mice

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“…The essentiality of both protamines for sperm chromatin rearrangement is evident from the extensive investigation using mouse models (Cho et al 2001, Mashiko et al 2013, Takeda et al 2016, Schneider et al 2020, Arévalo et al 2022, Merges et al 2022). However, it is still unclear why two protamines are required in some species whereas one protamine (PRM1) appears to be sufficient in others.…”

Section: The Protamine Ratiomentioning

confidence: 99%

“…Over the last two decades, several protamine-deficient mouse models have been generated using a variety of different approaches (Cho et al 2001, Mashiko et al 2013, Takeda et al 2016, Schneider et al 2020, Arévalo et al 2022, Merges et al 2022 (Cho et al 2001(Cho et al , 2003. Using homologous recombination, they generated Prm1 +/− and Prm2 +/− embryonic stem (ES) cells, which upon blastocyst injection produced several male and female chimeras.…”

Section: Protamine-deficient Mouse Modelsmentioning

confidence: 99%

Protamines: lessons learned from mouse models

et al. 2022

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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.

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Epigenetic aging of mammalian gametes

Klutstein,

Gonen

2023

Molecular Reproduction Devel

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The process of aging refers to physiological changes that occur to an organism as time progresses and involves changes to DNA, proteins, metabolism, cells, and organs. Like the rest of the cells in the body, gametes age, and it is well established that there is a decline in reproductive capabilities in females and males with aging. One of the major pathways known to be involved in aging is epigenetic changes. The epigenome is the multitude of chemical modifications performed on DNA and chromatin that affect the ability of chromatin to be transcribed. In this review, we explore the effects of aging on female and male gametes with a focus on the epigenetic changes that occur in gametes throughout aging. Quality decline in oocytes occurs at a relatively early age. Epigenetic changes constitute an important part of oocyte aging. DNA methylation is reduced with age, along with reduced expression of DNA methyltransferases (DNMTs). Histone deacetylases (HDAC) expression is also reduced, and a loss of heterochromatin marks occurs with age. As a consequence of heterochromatin loss, retrotransposon expression is elevated, and aged oocytes suffer from DNA damage. In sperm, aging affects sperm number, motility and fecundity, and epigenetic changes may constitute a part of this process. 5 methyl‐cytosine (5mC) methylation is elevated in sperm from aged men, but methylation on Long interspersed nuclear elements (LINE) elements is reduced. Di and trimethylation of histone 3 lysine 9 (H3K9me2/3) is reduced in sperm from aged men and trimethylation of histone 3 lysine 27 (H3K27me3) is elevated. The protamine makeup of sperm from aged men is also changed, with reduced protamine expression and a misbalanced ratio between protamine proteins protamine P1 and protamine P2. The study of epigenetic reproductive aging is recently gaining interest. The current status of the field suggests that many aspects of gamete epigenetic aging are still open for investigation. The clinical applications of these investigations have far‐reaching consequences for fertility and sociological human behavior.

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Loss of Prm1 leads to defective chromatin protamination, impaired PRM2 processing, reduced sperm motility and subfertility in male mice

Cited by 27 publications

References 66 publications

Loss of the cleaved-protamine 2 domain leads to incomplete histone-to-protamine exchange and infertility in mice

Loss of the cleaved-protamine 2 domain leads to incomplete histone-to-protamine exchange and infertility in mice

Protamines: lessons learned from mouse models

Epigenetic aging of mammalian gametes

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