Histone modification signatures in human sperm distinguish clinical abnormalities
Alternations to the paternal epigenome, specifically the components of sperm chromatin, can lead to infertility in humans and potentially transmit aberrant information to the embryo. One key component of sperm chromatin is the post-translational modification of histones (PTMs). We previously identified a comprehensive profile of histone PTMs in normozoospermic sperm; however, only specific histone PTMs have been identified in abnormal sperm by antibody-based approaches and comprehensive changes to histone PTM profiles remain unknown. Here, we investigate if sperm with abnormalities of total motility, progressive motility, and morphology have altered histone PTM profiles compared to normozoospermic sperm samples.
Discarded semen samples from 31 men with normal or abnormal semen parameters were analyzed for relative abundance of PTMs on histone H3 and H4 by “bottom-up” nano-liquid chromatography-tandem mass spectrometry.
Asthenoteratozoospermic samples (abnormal motility, forward progression, and morphology, n = 6) displayed overall decreased H4 acetylation (p = 0.001) as well as alterations in H4K20 (p = 0.003) and H3K9 methylation (p < 0.04) when compared to normozoospermic samples (n = 8). Asthenozoospermic samples (abnormal motility and progression, n = 5) also demonstrated decreased H4 acetylation (p = 0.04) and altered H4K20 (p = 0.005) and H3K9 methylation (p < 0.04). Samples with isolated abnormal progression (n = 6) primarily demonstrated decreased acetylation on H4 (p < 0.02), and teratozoospermic samples (n = 6) appeared similar to normozoospermic samples (n = 8).
Sperm samples with combined and isolated abnormalities of total motility, progressive motility, and morphology display distinct and altered histone PTM signatures compared to normozoospermic sperm. This provides evidence that alterations in histone PTMs may be important for normal sperm function and fertility.
KeywordsHistones Post-translational modifications Paternal epigenetics Sperm Male infertility
We would like to thank all of the staff at the Penn Fertility Care Andrology laboratory for their assistance, time, and effort in the de-identification of samples used in this study. In addition, we would like to thank The Penn Center for the Study of Epigenetics in Reproduction.
This work was funded by the National Institutes of Health Grants P50HD06817 (S.L.B./M.S.B./C.C/L.J.L), T32HD040135 (S.B.S/C.C), 5K12HD065257-07 (S.B.S), F32HD086939 (L.J.L.), and GM110174 (B.A.G).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflicts of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Approval for this study was obtained from the University of Pennsylvania Institutional Review Board (Protocol 815929).
As all samples were discarded and de-identified, the University of Pennsylvania Institutional Review Board determined that this study was exempt from requiring informed consent.
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