Abstract

Retrotransposons,mainlyLINEs,SINEs,andendogenousretroviruses,occupy40%ofthemammalian genome.Retrotransposonshaveanenormouscapacitytometastasizethroughoutthegenomeusinga?copy andpaste?mechanisminvolvingreversetranscription.Whileretrotransposonsplayanimportantrolein genomeevolution,theirmobilizationcanbedetrimentaltogenomeintegrity.Indeed,morethan60human geneticdiseasesarecausedbytransposoninsertion.Retrotransposonsexploitthehostcellularmachineryto proliferate.Inresponse,thehosthasevolvedmultiplemechanismstosuppressretrotransposonstoprotect genomeintegrity,particularlywithinthegermline.ThepiRNApathwayisamajorevolutionarilyconservedsmall non-codingRNA-basedsilencingmechanismforretrotransposonsingermcells.Inthepreviousfundingperiod, wedemonstratedthatMOV10L1,agermcell-specificRNAhelicase,isamasterregulatorofbiogenesisofall piRNAsinmouse.MOV10L1interactswithallPiwiproteinsandbindstopiRNAprecursorstoinitiatepiRNA biogenesis.DeficiencyofMov10l1leadstoupregulationofretrotransposons,ablockinmeiosis,andmale sterility.Upregulationofretrotransposontranscriptsdoesnotnecessarilyleadtoaproportionateincreasein newretrotransposition,suggestingthatadditionalhostfactorsblockretrotransposition.Whilepreviousstudies havemadetremendousprogressdelineatingmechanismsresponsiblefortranscriptionalandpost- transcriptionalsilencingofretrotransposons,hostrestrictionfactorsthatpreventgenomicintegrationof retrotransposonsinvivohavenotyetbeenidentified.Usingouruniquemousemodels,weplanto1) investigatethemolecularmechanismunderlyingtheessentialroleofMOV10L1inpiRNAbiogenesisduring spermatogenesis;?2)elucidatethecriticalroleofahostrestrictionfactorininhibitionofretrotranspositioninthe mousegermline;?3)interrogatethemulti-generationalimpactofretrotransposon-drivengenomeexpansionon genomestability,reproduction,anddiseases.Completionofthisprojectwillhavestrongimpactsonour understandingofretrotransposonsilencing,genomeexpansion,andetiologyofhumandiseasesincluding maleinfertility,pregnancyloss,andbirthdefects.

Public Health Relevance

Retrotransposonsarethemostabundantrepetitiveelementsinthemammaliangenome.Insertionof retrotransposonsintogenesdisruptstheirfunction,resultinginalargenumberofhumangeneticdiseases. Understandingretrotransposonmobilizationinthegermlineandacrossgenerationswillprovideinsightsinto genomeevolutionandtheetiologyofhumandiseasessuchasinfertility,pregnancyloss,andbirthdefects.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD069592-06A1
Application #
9823546
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Moss, Stuart B
Project Start
2012-05-01
Project End
2024-06-30
Budget Start
2019-08-02
Budget End
2020-06-30
Support Year
6
Fiscal Year
2019
Total Cost
Indirect Cost

  Institution

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

  Publications

Shi, Baolu; Xue, Jiangyang; Zhou, Jian et al. (2018) MORC2B is essential for meiotic progression and fertility. PLoS Genet 14:e1007175
Wang, P Jeremy (2017) Tracking LINE1 retrotransposition in the germline. Proc Natl Acad Sci U S A 114:7194-7196
Kasowitz, Seth D; Luo, Mengcheng; Ma, Jun et al. (2017) Embryonic lethality and defective male germ cell development in mice lacking UTF1. Sci Rep 7:17259
Silva, Sara; Homolka, David; Pillai, Ramesh S (2017) Characterization of the mammalian RNA exonuclease 5/NEF-sp as a testis-specific nuclear 3' ? 5' exoribonuclease. RNA 23:1385-1392
Fu, Qi; Pandey, Radha Raman; Leu, N Adrian et al. (2016) Mutations in the MOV10L1 ATP Hydrolysis Motif Cause piRNA Biogenesis Failure and Male Sterility in Mice. Biol Reprod 95:103
Yang, Fang; Wang, P Jeremy (2016) Multiple LINEs of retrotransposon silencing mechanisms in the mammalian germline. Semin Cell Dev Biol 59:118-125
Chen, Kuan-Ming; Campbell, Edgar; Pandey, Radha Raman et al. (2015) Metazoan Maelstrom is an RNA-binding protein that has evolved from an ancient nuclease active in protists. RNA 21:833-9
Vourekas, Anastassios; Zheng, Ke; Fu, Qi et al. (2015) The RNA helicase MOV10L1 binds piRNA precursors to initiate piRNA processing. Genes Dev 29:617-29
Fu, Qi; Wang, P Jeremy (2014) Mammalian piRNAs: Biogenesis, function, and mysteries. Spermatogenesis 4:e27889
Cora, Elisa; Pandey, Radha R; Xiol, Jordi et al. (2014) The MID-PIWI module of Piwi proteins specifies nucleotide- and strand-biases of piRNAs. RNA 20:773-81

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