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Genetic Control of Retrotransposon Mobilization in the Mouse Germline

小鼠种系中逆转录转座子动员的遗传控制

基本信息

批准号：
10651822
负责人：
Peijing Jeremy Wang
金额：
$ 33.04万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10651822
关键词：
Acceleration Binding Biogenesis C-terminal Cells Congenital Abnormality DNA DNA Methylation DNA Transposable Elements Development Disease Endogenous Retroviruses Ethylnitrosourea Etiology Evolution Fertility Frequencies Funding Future Gene Expression Gene Silencing Generations Genes Genetic Genetic Diseases Genetic Induction Genetic Transcription Genome Genome Stability Genomics Germ Cells Health Homologous Gene Human Genetics In Vitro Infertility Insertional Mutagenesis Integration Host Factors Junk DNA Knockout Mice Laboratories Lead Male Infertility Male Sterility Male Sterilizations Mediating Meiosis Methodology Missense Mutation Molecular Mus Mutagenesis Mutation N-terminal Neoplasm Metastasis Nuclear Import Organism Outcome Paste substance Pathway interactions Play Pregnancy loss Production Proliferating Proteins Publishing RNA RNA Helicase Repetitive Sequence Reporter Reproduction Retrotransposition Retrotransposon Reverse Transcription Ribonucleoproteins Role Short Interspersed Nucleotide Elements Spermatogenesis System Testing Testis Time Transcript Transgenes Up-Regulation arms race blocking factor gene function genome integrity human disease in vivo innovation insight mammalian genome mouse genome mouse model mutant novel particle piRNA posttranscriptional preservation prevent response

项目摘要

Project Summary Retrotransposons, mainly LINEs, SINEs, and endogenous retroviruses, occupy 40% of the mammalian genome. Retrotransposons have an enormous capacity to metastasize throughout the genome using a “copy and paste” mechanism involving reverse transcription. While retrotransposons play an important role in genome evolution, their mobilization can be detrimental to genome integrity. Indeed, more than 60 human genetic diseases are caused by transposon insertion. Retrotransposons exploit the host cellular machinery to proliferate. In response, the host has evolved multiple mechanisms to suppress retrotransposons to protect genome integrity, particularly within the germline. The piRNA pathway is a major evolutionarily conserved small non-coding RNA-based silencing mechanism for retrotransposons in germ cells. In the previous funding period, we demonstrated that MOV10L1, a germ cell-specific RNA helicase, is a master regulator of biogenesis of all piRNAs in mouse. MOV10L1 interacts with all Piwi proteins and binds to piRNA precursors to initiate piRNA biogenesis. Deficiency of Mov10l1 leads to upregulation of retrotransposons, a block in meiosis, and male sterility. Upregulation of retrotransposon transcripts does not necessarily lead to a proportionate increase in new retrotransposition, suggesting that additional host factors block retrotransposition. While previous studies have made tremendous progress delineating mechanisms responsible for transcriptional and post- transcriptional silencing of retrotransposons, host restriction factors that prevent genomic integration of retrotransposons in vivo have not yet been identified. Using our unique mouse models, we plan to 1) investigate the molecular mechanism underlying the essential role of MOV10L1 in piRNA biogenesis during spermatogenesis;; 2) elucidate the critical role of a host restriction factor in inhibition of retrotransposition in the mouse germline;; 3) interrogate the multi-generational impact of retrotransposon-driven genome expansion on genome stability, reproduction, and diseases. Completion of this project will have strong impacts on our understanding of retrotransposon silencing, genome expansion, and etiology of human diseases including male infertility, pregnancy loss, and birth defects.

项目总结

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Blockade of pachytene piRNA biogenesis reveals a novel requirement for maintaining post-meiotic germline genome integrity.

Pachytene PiRNA生物发生的阻断揭示了维持后寿命生殖基因组完整性的新需求。

DOI：
10.1371/journal.pgen.1003038
发表时间：
2012
期刊：
PLoS genetics
影响因子：
4.5
作者：
Zheng K;Wang PJ
通讯作者：
Wang PJ

Characterization of the mammalian RNA exonuclease 5/NEF-sp as a testis-specific nuclear 3' → 5' exoribonuclease.

DOI：
10.1261/rna.060723.117
发表时间：
2017-09
期刊：
RNA (New York, N.Y.)
影响因子：
0
作者：
Silva S;Homolka D;Pillai RS
通讯作者：
Pillai RS

MORC2B is essential for meiotic progression and fertility.

MORC2B 对于减数分裂进展和生育能力至关重要

DOI：
10.1371/journal.pgen.1007175
发表时间：
2018-01
期刊：
PLoS genetics
影响因子：
4.5
作者：
Shi B;Xue J;Zhou J;Kasowitz SD;Zhang Y;Liang G;Guan Y;Shi Q;Liu M;Sha J;Huang X;Wang PJ
通讯作者：
Wang PJ

Metazoan Maelstrom is an RNA-binding protein that has evolved from an ancient nuclease active in protists.