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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54HD068157-03
Application #
8446933
Study Section
Special Emphasis Panel (ZHD1-DSR-L)
Project Start
Project End
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
3
Fiscal Year
2013
Total Cost
$214,128
Indirect Cost
$80,298
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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
Meyer-Ficca, Mirella L; Ihara, Motomasa; Bader, Jessica J et al. (2015) Spermatid head elongation with normal nuclear shaping requires ADP-ribosyltransferase PARP11 (ARTD11) in mice. Biol Reprod 92:80
Bryant, Jessica M; Donahue, Greg; Wang, Xiaoshi et al. (2015) Characterization of BRD4 during mammalian postmeiotic sperm development. Mol Cell Biol 35:1433-48
Hu, Jialei; Donahue, Greg; Dorsey, Jean et al. (2015) H4K44 Acetylation Facilitates Chromatin Accessibility during Meiosis. Cell Rep 13:1772-80
Butts, Samantha F; Guidotti, Tee L (2014) What are some potential reproductive hazards in the hospital environment? J Occup Environ Med 56:e163-5
Ihara, Motomasa; Meyer-Ficca, Mirella L; Leu, N Adrian et al. (2014) Paternal poly (ADP-ribose) metabolism modulates retention of inheritable sperm histones and early embryonic gene expression. PLoS Genet 10:e1004317
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
Butts, Samantha F; Owen, Carter; Mainigi, Monica et al. (2014) Assisted hatching and intracytoplasmic sperm injection are not associated with improved outcomes in assisted reproduction cycles for diminished ovarian reserve: an analysis of cycles in the United States from 2004 to 2011. Fertil Steril 102:1041-1047.e1
Butts, Samantha F; Ratcliffe, Sarah; Dokras, Anuja et al. (2013) Diagnosis and treatment of diminished ovarian reserve in assisted reproductive technology cycles of women up to age 40 years: the role of insurance mandates. Fertil Steril 99:382-8
Butts, Samantha F; Guo, Wensheng; Cary, Mark S et al. (2013) Predicting the decline in human chorionic gonadotropin in a resolving pregnancy of unknown location. Obstet Gynecol 122:337-43

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