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.
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.
|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|
|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|
|Bryant, Jessica M; Donahue, Greg; Wang, Xiaoshi et al. (2015) Characterization of BRD4 during mammalian postmeiotic sperm development. Mol Cell Biol 35:1433-48|
|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|
|Hu, Jialei; Donahue, Greg; Dorsey, Jean et al. (2015) H4K44 Acetylation Facilitates Chromatin Accessibility during Meiosis. Cell Rep 13:1772-80|
|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; 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; 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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