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. 2025 Dec;20(1):2498859.
doi: 10.1080/15592294.2025.2498859. Epub 2025 Apr 29.

Higher sperm H3K4me3 levels are associated with idiopathic recurrent pregnancy loss

Delna Irani  1 , Deepshikha Arya  1 , Deepti Tandon  2 , Vandana Bansal  3 , Anushree Patil  2   4 , Dipty Singh  1   4
Affiliations

Higher sperm H3K4me3 levels are associated with idiopathic recurrent pregnancy loss

Delna Irani et al. Epigenetics. 2025 Dec.

Abstract

During fertilization, spermatozoa contribute genetic and epigenetic factors such as chromatin packaged with protamines and histones; DNA methylome, non-coding RNAs, etc. Human sperm chromatin retains 5-15% nucleosomes which can play a key role in embryonic development. Recurrent pregnancy loss (RPL) is a condition mainly attributed to defects in embryo and placenta development. Majority of the known RPL factors are of maternal contribution, while ~50% RPL cases are termed idiopathic (iRPL). In addition to paternal genetic factors, epigenetic factors via sperm could also be responsible for iRPL. Hence, we investigated alterations in retained nucleosome content of iRPL sperm (n = 46) as compared to fertile male population (n = 40). We measured the relative abundance of core histone H4 and Protamine-2 content along with the modified histones H4Ac, H3K4me3, H3K27me3 and H3K9me3 by flow cytometry. H4 and Protamine-2 levels were comparable in both groups and showed significant negative correlation. The iRPL group had significantly higher levels of sperm H3K4me3 as compared to the fertile control group. The other modified histones and protamine levels showed no significant alterations. Furthermore, sperm DFI was found to be significantly positively correlated with H4 levels in both groups. No significant correlation was observed between sperm 5-mC levels with H4 and other modified histone levels. A fraction of H3K4me3 enrichment is now known to resist embryonic epigenetic reprogramming; and hence, such elevated levels in the sperm would question its developmental competence leading to RPL pathology. Also, incidence of sperm DNA fragmentation is associated with increased histone retention in both fertile and iRPL cases.

Keywords: 5-mC; H3K4me3; Idiopathic recurrent pregnancy loss; sperm DNA fragmentation; sperm histones.

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Conflict of interest statement

No potential conflict of interest was reported by the author(s).

Figures

Figure 1.
Figure 1.
Relative levels of core histone H4 and Protamine-2 in sperm.
Figure 2.
Figure 2.
Relative levels of modified histones in sperm.
Figure 3.
Figure 3.
Correlation analysis of sperm H4 levels with sperm DFI% and 5-mC%.
Figure 4.
Figure 4.
Correlation analysis of sperm modified histones with sperm 5-mC%.
See this image and copyright information in PMC

References

    1. Bender Atik R, Christiansen OB, Elson J, et al. ESHRE guideline: recurrent pregnancy loss. Hum Reprod Open. 2018;2018(2):1–15. doi: 10.1093/hropen/hoy004 - DOI - PMC - PubMed
    1. Ticconi C, Di Simone N, Campagnolo L, et al. Clinical consequences of defective decidualization. Tissue Cell. 2021;72:101586. doi: 10.1016/j.tice.2021.101586 - DOI - PubMed
    1. Ibrahim Y, Johnstone E.. The male contribution to recurrent pregnancy loss. Transl Androl Urol. 2018;7(S3):S317–27. doi: 10.21037/tau.2018.05.14 - DOI - PMC - PubMed
    1. Yu W, Bao S. Association of male factors with recurrent pregnancy loss. J Reprod Immunol. 2022;154:103758. doi: 10.1016/j.jri.2022.103758 - DOI - PubMed
    1. McGrath J, Solter D. Completion of mouse embryogenesis requires both the maternal and paternal genomes. Cell. 1984;37(1):179–183. doi: 10.1016/0092-8674(84)90313-1 - DOI - PubMed

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