The PIWI interaction RNA (piRNA) pathway is required for transposon silencing during germline development in flies, fish and mouse. The 24 to 29 nucleotide long piRNAs are produced by a Dicer-independent mechanism and associate specifically with PIWI class Argonaute proteins. These piRNA-PIWI complexes can cleave target RNAs in vitro. However, the in vivo mechanism of transposon silencing and the genomic origins of piRNAs are not understood. In addition, the full spectrum of biological functions for the piRNA pathway remains to be explored. These broad questions will be addressed using a combination of genetic, genomic, cytological and molecular approaches in the experimentally tractable Drosophila system. The broad aims of the proposal are to define the structural and biochemical properties of piRNA encoding clusters, determine the mechanism of transposon silencing by piRNAs, and to characterize recently identified functions for this pathway in meiotic and mitotic chromosome segregation. Studies under aim 1 will use computational analysis of deep sequencing data and chromatin immunoprecipitation to define properties of piRNA encoding clusters.
Aim 2 will use transgenic reporters to explore the mechanism of piRNA silencing. Studies under Aim 3 will use genetic, molecular and cytological approaches to define the role of piRNA in telomere protection and chromosome segregation.

Public Health Relevance

Transposon are mobile genetic elements that make up almost 50% of the human genome. Mobilization of these elements can cause genetic diseases, including cancer. piRNAs have a conserved function in maintaining genome integrity and suppressing transposon mobilization. The long term goal of the proposed studies is to understand how piRNA control the transposon activity.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD049116-10
Application #
8610163
Study Section
Development - 1 Study Section (DEV1)
Program Officer
Taymans, Susan
Project Start
2004-12-01
Project End
2015-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
10
Fiscal Year
2014
Total Cost
$539,952
Indirect Cost
$211,715
Name
University of Massachusetts Medical School Worcester
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Zhang, Zhao; Koppetsch, Birgit S; Wang, Jie et al. (2014) Antisense piRNA amplification, but not piRNA production or nuage assembly, requires the Tudor-domain protein Qin. EMBO J 33:536-9
Zhang, Zhao; Wang, Jie; Schultz, Nadine et al. (2014) The HP1 homolog rhino anchors a nuclear complex that suppresses piRNA precursor splicing. Cell 157:1353-63
Zhuang, Jiali; Wang, Jie; Theurkauf, William et al. (2014) TEMP: a computational method for analyzing transposable element polymorphism in populations. Nucleic Acids Res 42:6826-38
Simkin, Alfred; Wong, Alex; Poh, Yu-Ping et al. (2013) Recurrent and recent selective sweeps in the piRNA pathway. Evolution 67:1081-90
Perrat, Paola N; DasGupta, Shamik; Wang, Jie et al. (2013) Transposition-driven genomic heterogeneity in the Drosophila brain. Science 340:91-5
Zhang, Zhao; Xu, Jia; Koppetsch, Birgit S et al. (2011) Heterotypic piRNA Ping-Pong requires qin, a protein with both E3 ligase and Tudor domains. Mol Cell 44:572-84
Khurana, Jaspreet S; Xu, Jia; Weng, Zhiping et al. (2010) Distinct functions for the Drosophila piRNA pathway in genome maintenance and telomere protection. PLoS Genet 6:e1001246
Klattenhoff, Carla; Xi, Hualin; Li, Chengjian et al. (2009) The Drosophila HP1 homolog Rhino is required for transposon silencing and piRNA production by dual-strand clusters. Cell 138:1137-49
Li, Chengjian; Vagin, Vasily V; Lee, Soohyun et al. (2009) Collapse of germline piRNAs in the absence of Argonaute3 reveals somatic piRNAs in flies. Cell 137:509-21
Benoit, Beatrice; He, Chun Hua; Zhang, Fan et al. (2009) An essential role for the RNA-binding protein Smaug during the Drosophila maternal-to-zygotic transition. Development 136:923-32

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