Samantha B Schon1,2, Lacey J Luense3,4, Xiaoshi Wang4,5, Marisa S Bartolomei3,4, Christos Coutifaris6, Benjamin A Garcia4,5, Shelley L Berger7,8. 1. Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Pennsylvania, 3701 Market Street, Suite 800, Philadelphia, PA, 19104, USA. sschon@umich.edu. 2. Division of Reproductive Endocrinology & Infertility, Department of Obstetrics and Gynecology, University of Michigan Medical School, L4000 UH-South, 1500 E. Medical Center Drive, Ann Arbor, MI, 48109, USA. sschon@umich.edu. 3. Department of Cell and Developmental Biology, Perelman School of Medicine, 9-125 Smilow Center for Translational Research, University of Pennsylvania, 3400 Civic Center Blvd, Bldg 421, Philadelphia, PA, 19104-6058, USA. 4. Epigenetics Institute, Perelman School of Medicine, 9-125 Smilow Center for Translational Research, University of Pennsylvania, 3400 Civic Center Blvd, Bldg 421, Philadelphia, PA, 19104-6058, USA. 5. Department of Biochemistry and Molecular Biophysics, Perelman School of Medicine, 9-125 Smilow Center for Translational Research, University of Pennsylvania, 3400 Civic Center Blvd, Bldg 421, Philadelphia, PA, 19104, USA. 6. Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Pennsylvania, 3701 Market Street, Suite 800, Philadelphia, PA, 19104, USA. 7. Department of Cell and Developmental Biology, Perelman School of Medicine, 9-125 Smilow Center for Translational Research, University of Pennsylvania, 3400 Civic Center Blvd, Bldg 421, Philadelphia, PA, 19104-6058, USA. bergers@upenn.edu. 8. Epigenetics Institute, Perelman School of Medicine, 9-125 Smilow Center for Translational Research, University of Pennsylvania, 3400 Civic Center Blvd, Bldg 421, Philadelphia, PA, 19104-6058, USA. bergers@upenn.edu.
Abstract
PURPOSE: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.
PURPOSE: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.
Entities:
Keywords:
Histones; Male infertility; Paternal epigenetics; Post-translational modifications; Sperm
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