Abstract

Germcellsundergoextensiveepigeneticreprogrammingduringdevelopment.Duringthiscriticalperiod, retrotransposonsarereactivatedduetogenome-wideerasureofDNAmethylationandarere-silencedbyde novoDNAmethylation.Retrotransposons,mainlyLINEs,SINEs,andendogenousretroviruses(collectively referredtoasjunkDNA),occupy40%ofthemammaliangenome.Althoughretrotransposonsplayan importantroleingenomeevolution,theirmobilizationcouldbedetrimentaltogenomeintegrity.Multiple epigeneticmechanismsareresponsibleforsilencingretrotransposonsinthegermline:DNAmethylation, repressivehistonemodification,smallRNAs,andheterochromatinization.Giventheextremeabundanceofthe retrotransposonsandtheparamountimportanceofgermlinegenomeintegrity,novelmechanismsfor retrotransposonsilencingmayexist.Insupport,wehavefoundthatTEX15,agermcell-specific3059-aa proteinwithanewlyidentifiedfunctionaldomain,isrequiredformeiosisandmalefertility,andisanovel epigeneticregulatoressentialforretrotransposonsilencing.Basedonthesedata,wehypothesizethatTEX15 isanovelgermcell-specificregulatorofretrotransposonactivationandthatmeioticcollapseisthe ultimate?fail-safe?mechanismforpreventingtransmissionofmalegermcellsinwhich retrotransposonsareinordinatelyactivated.Inthisproject,wewill1)determinetheTEX15-mediated epigeneticlandscapeduringmalegermcelldevelopmentinmouseusinggenomicapproaches,2)elucidate molecularmechanismsunderlyingTEX15function,and3)screenforretrotransposonactivationandutilize wholeexomesequencingtoidentifygeneticmutationsthatcompromiseepigeneticsilencingof retrotransposonsintestisbiopsiesfromazoospermicmen.Together,thesestudieswillidentifynovelfactorsin thesilencingofretrotransposonsandprovideessentialinsightsintotheetiologyofmaleinfertilityinhumans.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Specialized Center (P50)
Project #
2P50HD068157-06A1
Application #
9605495
Study Section
Special Emphasis Panel (ZHD1)
Project Start
Project End
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
6
Fiscal Year
2018
Total Cost
Indirect Cost

  Institution

Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104

  Publications

Ghosh, Jayashri; Coutifaris, Christos; Sapienza, Carmen et al. (2017) Global DNA methylation levels are altered by modifiable clinical manipulations in assisted reproductive technologies. Clin Epigenetics 9:14
Vrooman, Lisa A; Bartolomei, Marisa S (2017) Can assisted reproductive technologies cause adult-onset disease? Evidence from human and mouse. Reprod Toxicol 68:72-84
Weinerman, Rachel; Ord, Teri; Bartolomei, Marisa S et al. (2017) The superovulated environment, independent of embryo vitrification, results in low birthweight in a mouse model. Biol Reprod 97:133-142
Vrooman, Lisa A; Xin, Frances; Bartolomei, Marisa S (2016) Morphologic and molecular changes in the placenta: what we can learn from environmental exposures. Fertil Steril 106:930-40
Ghosh, Jayashri; Mainigi, Monica; Coutifaris, Christos et al. (2016) Outlier DNA methylation levels as an indicator of environmental exposure and risk of undesirable birth outcome. Hum Mol Genet 25:123-9
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
Weinerman, Rachel; Feng, Rui; Ord, Teri S et al. (2016) Morphokinetic Evaluation of Embryo Development in a Mouse Model: Functional and Molecular Correlates. Biol Reprod 94:84
Castle, Megan; Cleveland, Charlotte; Gordon, Diana et al. (2016) Reproductive Science for High School Students: A Shared Curriculum Model to Enhance Student Success. Biol Reprod 95:28
Luense, Lacey J; Wang, Xiaoshi; Schon, Samantha B et al. (2016) Comprehensive analysis of histone post-translational modifications in mouse and human male germ cells. Epigenetics Chromatin 9:24

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