Contribution of the paternal histone epigenome to embryo development and pregnancy loss

PROJECT SUMMARY Pregnancy loss is estimated to affect approximately 30% of clinically defined pregnancies in the United States, however the actual number is likely much higher due to spontaneous abortions prior to a woman learning she is pregnant. Similarly, in cattle, almost 50% of pregnancies are estimated to end prematurely. In both species, the majority of pregnancies are lost early in embryonic development and the underlying reason is often unknown or unexplained. One potential mechanism underlying pregnancy loss are alterations to the paternal epigenome. Mammalian spermatozoa exhibit a unique, highly compacted and condensed DNA structure that is strongly dependent on epigenetic mechanisms, including histone hyperacetylation followed by nucleosome eviction. Specifically, 85-99% of sperm nucleosomes are evicted and replaced with protamines, allowing for this remarkable degree of compaction. Human sperm exhibiting abnormal chromatin composition, including excess histone retention or post-translational modifications, are associated with infertility, altered embryogenesis following IVF/ICSI, and pregnancy loss. However, the exact cause of altered embryogenesis as a result of an abnormal paternal epigenome, and ultimately, potential regulatory functions and mechanisms by which paternally contributed histones affect early development, remain largely unknown. In this proposal, sperm from bulls of low fertility that have previously been linked to pregnancy loss will be utilized to understand how sperm chromatin regulates mammalian fertility, embryogenesis, and establishment of a healthy pregnancy. This proposal will test if the paternal contribution of epigenetic information, specifically histones, associated post-translational modifications, and genomic placement, are a critical factor in normal embryo development, placentation, and ultimately successful pregnancy. These studies will utilize previously characterized bulls of high and low fertility to study the paternal histone epigenome and subsequent regulation of the embryo though the following Specific Aims: (1) Establish the baseline paternal histone epigenome in fertile bulls (2) Determine if the paternal histone epigenome is altered in low-fertility bulls and (3) Investigate changes to preimplantation embryos generated from low-fertility bulls. Together, the proposed research will provide important insight into the mechanisms governing early embryonic development, including the effects of an abnormal paternal epigenome on chromatin dynamics and embryonic genome activation. It will additionally provide evidence as to why paternal chromatin results in infertility and altered embryogenesis in cattle and humans. The results of these studies have the potential to ultimately impact reproductive efficiency and help clinical management of patients diagnosed with infertility, poor embryogenesis, and pregnancy loss.