Dynamic epigenetic alteration is central to differentiation of mammalian sperm, however the nature of these changes largely remains unknown. We propose that sequentially altered patterns of histone posttranslational modifications underlies chromatin restructuring during spermatogenesis and in mature sperm. We previously used sporulation in budding yeast S. cerevisiae, as a tractable model for gametogenesis, to uncover dynamic histone modifications, and then examined these in mouse spermatogenesis. Our data indicate that mouse sperm development involves temporal sequences of histone modifications, including multiple novel modifications, which are analogous in timing to the yeast. This conservation of the pattern of histone modifications during gametogenesis from yeast to mammals, strongly indicates that epigenetic regulation is key to the normal process of chromatin restructuring during gametogenesis. As part of the U54 Center, we will investigate novel epigenetic regulatory pathways in normal and abnormal mammalian spermatogenesis, in the mouse model and in human samples. Our hypothesis is that chromatin modulation is a highly evolutionarily conserved process in gametogenesis, is a key regulatory feature of spermatogenesis, and is altered in abnormal sperm, including in human infertility. We will investigate histone modifications during normal and abnormal spermatogenesis in the mouse model in collaboration with Project IV, and will examine sperm from human samples to determine whether modifications are altered, in collaboration with Project I.
Our specific aims are: (1) to investigate histone post-translational modifications during mouse spermatogenesis, (2) to determine whether histone post-translation modifications are altered in mouse models having deregulated poly(ADP-ribose) (PAR) metabolism, and (3) to compare normal and abnormal human sperm from clinical IVF samples to discover potential disruptions of histone posttranslational modifications. Collaborations within our proposed Center provide unique synergistic approaches and research materials to uncover novel epigenetic pathways in normal and abnormal spermatogenesis, including in clinical human male infertility.

Public Health Relevance

We previously discovered novel epigenetic modifications during mouse spermatogenesis. In this proposal, we will collaborate within the U54 Center to examine epigenetic changes in normal and abnormal mammalian spermatogenesis, including in human mature sperm. Results from this study will ultimately provide new diagnostic information about epigenetic regulation and dysfunction in human spermatogenesis.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZHD1-DSR-L)
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University of Pennsylvania
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Hur, Stella K; Freschi, Andrea; Ideraabdullah, Folami et al. (2016) Humanized H19/Igf2 locus reveals diverged imprinting mechanism between mouse and human and reflects Silver-Russell syndrome phenotypes. Proc Natl Acad Sci U S A 113:10938-43
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Mainigi, Monica A; Olalere, Devvora; Burd, Irina et al. (2014) Peri-implantation hormonal milieu: elucidating mechanisms of abnormal placentation and fetal growth. Biol Reprod 90:26
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