Genome-wide analysis identifies changes in histone retention and epigenetic modifications at developmental and imprinted gene loci in the sperm of infertile men
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Open Access
- 17 June 2011
- journal article
- research article
- Published by Oxford University Press (OUP) in Human Reproduction
- Vol. 26 (9), 2558-2569
- https://doi.org/10.1093/humrep/der192
Abstract
The sperm chromatin of fertile men retains a small number of nucleosomes that are enriched at developmental gene promoters and imprinted gene loci. This unique chromatin packaging at certain gene promoters provides these genomic loci the ability to convey instructive epigenetic information to the zygote, potentially expanding the role and significance of the sperm epigenome in embryogenesis. We hypothesize that changes in chromatin packaging may be associated with poor reproductive outcome. Seven patients with reproductive dysfunction were recruited: three had unexplained poor embryogenesis during IVF and four were diagnosed with male infertility and previously shown to have altered protamination. Genome-wide analysis of the location of histones and histone modifications was analyzed by isolation and purification of DNA bound to histones and protamines. The histone-bound fraction of DNA was analyzed using high-throughput sequencing, both initially and following chromatin immunoprecipitation. The protamine-bound fraction was hybridized to agilent arrays. DNA methylation was examined using bisulfite sequencing. Unlike fertile men, five of seven infertile men had non-programmatic (randomly distributed) histone retention genome-wide. Interestingly, in contrast to the total histone pool, the localization of H3 Lysine 4 methylation (H3K4me) or H3 Lysine 27 methylation (H3K27me) was highly similar in the gametes of infertile men compared with fertile men. However, there was a reduction in the amount of H3K4me or H3K27me retained at developmental transcription factors and certain imprinted genes. Finally, the methylation status of candidate developmental promoters and imprinted loci were altered in a subset of the infertile men. This initial genome-wide analysis of epigenetic markings in the sperm of infertile men demonstrates differences in composition and epigenetic markings compared with fertile men, especially at certain imprinted and developmental loci. Although no single locus displays a complete change in chromatin packaging or DNA modification, the data suggest that moderate changes throughout the genome exist and may have a cumulative detrimental effect on fecundity.This publication has 35 references indexed in Scilit:
- Selective loss of imprinting in the placenta following preimplantation development in cultureDevelopment, 2004
- Genomic imprinting in disruptive spermatogenesisThe Lancet, 2004
- Assisted Reproductive Technology in the United StatesThe New England Journal of Medicine, 2004
- A prospective longitudinal study of the physical, psychomotor, and intellectual development of singleton children up to 5 years who were conceived by intracytoplasmic sperm injection compared with children conceived spontaneously and by in vitro fertilizationFertility and Sterility, 2003
- Association of In Vitro Fertilization with Beckwith-Wiedemann Syndrome and Epigenetic Alterations of LIT1 and H19American Journal of Human Genetics, 2003
- Intracytoplasmic Sperm Injection May Increase the Risk of Imprinting DefectsAmerican Journal of Human Genetics, 2002
- The Risk of Major Birth Defects after Intracytoplasmic Sperm Injection and in Vitro FertilizationThe New England Journal of Medicine, 2002
- Altered Protamine 2 Expression Is Uncommon In Donors of Known Fertility, but Common Among Men With Poor Fertilizing Capacity, and May Reflect Other Abnormalities of SpermiogenesisJournal of Andrology, 2001
- Culture of Preimplantation Mouse Embryos Affects Fetal Development and the Expression of Imprinted Genes1Biology of Reproduction, 2001
- Maternal methylation imprints on human chromosome 15 are established during or after fertilizationNature Genetics, 2001