It is not well understood how metabolic and dietary deficiencies during male germ cell development interfere with the establishment of correct epigenetic marks in mature sperm that will support fertilization and proper embryonic development. This gap is an important problem hindering the development of novel strategies to improve poor sperm quality and prevent paternally transmitted epigenetic disorders. Based on compelling preliminary data, the central hypothesis to be tested is that the pharmacologically tractable poly(ADP-ribose) (PAR) pathway is necessary for proper epigenetic pattern formation in the male germ line. Therefore, three specific aims will be pursued: 1.Determine to what extent PAR metabolism is involved in the erasure of epigenetic chromatin modifications in male primordial germ cells (PGCs). Mice with genetically and pharmacologically perturbed PAR metabolism will be used to study the involvement of PAR polymerases 1 and 2 (PARPI, PARP2) in DNA repair dependent active DNA demethylation and elimination of histones with posttranslational modifications in male PGCs. This will be done in collaboration with Dr. Bartolomei's (Project #11) and Dr. Berger's (Project #111) groups, respectively. 2. Evaluate to which extent de novo establishment and maintenance of DNA methylation patterns is dependent on intact PAR metabolism. Investigations here are aimed at elucidation of PAR functions in de novo and maintenance DNA methylation involving insulator proteins and DNA methyltransferases 1, 3a and 3b during testis development and spermatogenesis. 3. Define the impact of PAR metabolism inhibition during male germ cell development on DNA methylation patterns of mature sperm. Partnering with Dr. Coutifari's group (Project #1), it will be assessed how disrupting PAR metabolism during early mouse germ cell development causes specific epigenetic abnormalities later in mature sperm that can be also found in patients with idiopathic subfertility. This approach is innovative because it will test a new paradigm with relevance to public health. The proposed research is significant because it should aid further refinement of ART procedures and at the same time advance our understanding of environmental impacts on epigenetic events in the germ line that are potentially associated with late-onset diseases in the next generation.

Public Health Relevance

The proposed research is relevant to public health because the discovery of a novel, conserved mechanism is ultimately expected to increase understanding of the pathogenesis of late-onset diseases caused environmental or dietary factors as well as risk prediction for such disorders. Therfore, the proposed work is relevant to NlH's mission to develop fundamental knowledge that will help to reduce the burdens of illness.

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 #
5U54HD068157-02
Application #
8377937
Study Section
Special Emphasis Panel (ZHD1-DSR-L)
Project Start
Project End
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
2
Fiscal Year
2012
Total Cost
$140,984
Indirect Cost
$66,930
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Smoak, Evan M; Stein, Paula; Schultz, Richard M et al. (2016) Long-Term Retention of CENP-A Nucleosomes in Mammalian Oocytes Underpins Transgenerational Inheritance of Centromere Identity. Curr Biol 26:1110-6
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Hu, Jialei; Donahue, Greg; Dorsey, Jean et al. (2015) H4K44 Acetylation Facilitates Chromatin Accessibility during Meiosis. Cell Rep 13:1772-80
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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; 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

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