PROJECT 4: TARGETING ADP-RIBOSE POLYMER DEPENDENT EPIGENETIC EVENTS IN MALE LINE

University Of Pennsylvania, Philadelphia PA

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Abstract

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.