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Guarding the Germ-line Stem Cell Genome: Biogenesis and Function of Piwi-Interacting RNAs (piRNAs)

Guarding the Germ-line Stem Cell Genome
Reported by
Keith Mulvihill

Posted January 11, 2011


Despite relatively frequent mutations to their genome, organisms manage to suppress the high levels of phenotypic variation that would otherwise accompany these mutations. Scientists believe this ability to maintain the germline genome in the face of environmental influence is related to the functioning of a recently discovered class of small non-coding RNA called Piwi-interacting RNA (piRNA). These small regulatory RNA molecules bind to specialized proteins, called "Piwi" proteins, from the Argonaute family, but their biogenesis and mechanisms of action still remain largely a mystery.

At a half-day meeting on November 3rd, 2010 scientists met at the New York Academy of Sciences to discuss the burgeoning body of research on these intriguing molecular actors. In their presentations researchers covered everything from the discovery of piRNAs and Piwi proteins in human fetal oocytes and in neuronal cells of Aplysia to these molecules' role in both genome maintenance and gene expression. Though there is much left to understand about, among other properties, the structural features of piRNAs and their targets, their role in epigenetic regulation, and their potential influence on congenital diseases, it is clear from this symposium's talks that piRNAs play a crucial role in guarding the germline.

Use the tabs above to find a meeting report and multimedia from this event.


Stefan Ameres

Ameres SL, Horwich MD, Hung J, et al. Target RNA-directed trimming and tailing of small silencing RNAs. Science 2010; 328(5985):1534-1539.

Ameres SL, Hung J, Xu J, Weng Z, Zamore PD. Target RNA-directed tailing and trimming purifies the sorting of endo-siRNAs between the two Drosophila Argonaute proteins. RNA 2011; 17(1):54-63.

Czech B, Malone CD, Zhou R, et al. An endogenous small interfering RNA pathway in Drosophila. Nature 2008; 453(7196):798-802.

Czech B, Zhou R, Erlich Y, et al. Hierarchical rules for Argonaute loading in Drosophila. Mol. Cell 2009; 36(3):445-456.

Horwich MD, Li C, Matranga C, et al. The Drosophila RNA methyltransferase, DmHen1, modifies germline piRNAs and single-stranded siRNAs in RISC. Curr. Biol. 2007; 17(14):1265-1272.

Okamura K, Chung W, Ruby JG, et al. The Drosophila hairpin RNA pathway generates endogenous short interfering RNAs. Nature 2008; 453(7196):803-806.

Weifeng Gu

Conine CC, Batista PJ, Gu W, et al. Argonautes ALG-3 and ALG-4 are required for spermatogenesis-specific 26G-RNAs and thermotolerant sperm in Caenorhabditis elegans. Proc. Natl. Acad. Sci. USA 2010; 107(8):3588-3593.

Gu W, Shirayama M, Conte D, et al. Distinct argonaute-mediated 22G-RNA pathways direct genome surveillance in the C. elegans germline. Mol. Cell 2009; 36(2):231-244.

Lee H, Li L, Gu W, et al. Diverse pathways generate microRNA-like RNAs and Dicer-independent small interfering RNAs in fungi. Mol. Cell 2010; 38(6):803-814.

Vasale JJ, Gu W, Thivierge C, et al. Sequential rounds of RNA-dependent RNA transcription drive endogenous small-RNA biogenesis in the ERGO-1/Argonaute pathway. Proc. Natl. Acad. Sci. USA 2010; 107(8):3582-3587.

Nelson Lau

Lau NC. Analysis of small endogenous RNAs. Curr. Protoc. Mol. Biol. 2008; Chapter 26: Unit 26.7.

Lau NC. Small RNAs in the animal gonad: guarding genomes and guiding development. Int. J. Biochem. Cell Biol. 2010; 42(8):1334-1347.

Lau NC, Robine N, Martin R, et al. Abundant primary piRNAs, endo-siRNAs, and microRNAs in a Drosophila ovary cell line. Genome Res. 2009; 19(10):1776-1785.

Malone CD, Brennecke J, Dus M, et al. Specialized piRNA pathways act in germline and somatic tissues of the Drosophila ovary. Cell 2009; 137(3):522-535.

Nei M, Niimura Y, Nozawa M. The evolution of animal chemosensory receptor gene repertoires: roles of chance and necessity. Nat. Rev. Genet. 2008; 9(12):951-963.

Robine N, Lau NC, Balla S, et al. A broadly conserved pathway generates 3′UTR-directed primary piRNAs. Curr. Biol. 2009; 19(24):2066-2076.

Haifan Lin

Gangaraju VK, Lin H. MicroRNAs: key regulators of stem cells. Nat. Rev. Mol. Cell Biol. 2009; 10(2):116-125.

Ma Y, Jin J, Dong C, et al. High-efficiency siRNA-based gene knockdown in human embryonic stem cells. RNA 2010; 16(12):2564-2569.

Qi H, Watanabe T, Ku H, et al. The Yb body, a major site for piRNA biogenesis and a gateway for Piwi expression and transport to the nucleus in somatic cells. J. Biol. Chem. 2010.

Smulders-Srinivasan TK, Szakmary A, Lin H. A Drosophila chromatin factor interacts with the Piwi-interacting RNA mechanism in niche cells to regulate germline stem cell self-renewal. Genetics 2010; 186(2):573-583.

Ye Y, Yin D, Chen L, et al. Identification of Piwil2-like (PL2L) proteins that promote tumorigenesis. PLoS ONE 2010; 5(10):e13406.

Zissimos Mourelatos

Kirino Y, Kim N, de Planell-Saguer M, et al. Arginine methylation of Piwi proteins catalysed by dPRMT5 is required for Ago3 and Aub stability. Nat. Cell Biol. 2009;11(5):652-658.

Kirino Y, Vourekas A, Sayed N, et al. Arginine methylation of Aubergine mediates Tudor binding and germ plasm localization. RNA 2010; 16(1):70-78.

Nelson PT, Kiriakidou M, Mourelatos Z, et al. High-throughput experimental studies to identify miRNA targets directly, with special focus on the mammalian brain. Brain Res. 2010; 1338:122-130.

Vourekas A, Kirino Y, Mourelatos Z. Elective affinities: a Tudor-Aubergine tale of germline partnership. Genes Dev. 2010; 24(18):1963-1966.

Priya Rajasethupathy

Cui Y, Rajasethupathy P, Hess GP. Selection of stable RNA molecules that can regulate the channel-opening equilibrium of the membrane-bound gamma-aminobutyric acid receptor. Biochemistry 2004; 43(51):16442-16449.

Rajasethupathy P, Fiumara F, Sheridan R, et al. Characterization of small RNAs in Aplysia reveals a role for miR-124 in constraining synaptic plasticity through CREB. Neuron 2009; 63(6):803-817.

Haruhiko Siomi

Miyoshi K, Miyoshi T, Siomi H. Many ways to generate microRNA-like small RNAs: non-canonical pathways for microRNA production. Mol. Genet. Genomics 2010; 284(2):95-103.

Nagao A, Mituyama T, Huang H, et al. Biogenesis pathways of piRNAs loaded onto AGO3 in the Drosophila testis. RNA 2010; 16(12):2503-2515.

Saito K, Inagaki S, Mituyama T, et al. A regulatory circuit for piwi by the large Maf gene traffic jam in Drosophila. Nature 2009; 461(7268):1296-1299.

Saito K, Ishizu H, Komai M, et al. Roles for the Yb body components Armitage and Yb in primary piRNA biogenesis in Drosophila. Genes Dev. 2010; 24(22):2493-2498.

Siomi MC, Mannen T, Siomi H. How does the royal family of Tudor rule the PIWI-interacting RNA pathway? Genes Dev. 2010; 24(7):636-646.

Siomi MC, Miyoshi T, Siomi H. piRNA-mediated silencing in Drosophila germlines. Semin. Cell Dev. Biol. 2010; 21(7):754-759.

Zev Williams

Aravin AA, Hannon GJ, Brennecke J. The Piwi-piRNA pathway provides an adaptive defense in the transposon arms race. Science 2007; 318(5851):761-764.

Farazi TA, Juranek SA, Tuschl T. The growing catalog of small RNAs and their association with distinct Argonaute/Piwi family members. Development 2008; 135(7):1201-1214.

Tam OH, Aravin AA, Stein P, et al. Pseudogene-derived small interfering RNAs regulate gene expression in mouse oocytes. Nature 2008; 453(7194):534-538.


Eric Lai
Eric Lai, PhD

Memorial Sloan–Kettering Cancer Center
e-mail | web site | publications

Eric Lai received his BA from Harvard University and performed thesis work in the laboratory of Gary Ruvkun, where he learned about developmental gene regulation in C. elegans. He did his PhD at UC San Diego with James Posakony on Drosophila neural patterning and Notch signaling, and continued to study these topics as a postdoc with Gerald Rubin at UC Berkeley. He joined the faculty of Sloan–Kettering Institute in 2005. His laboratory studies diverse topics related to developmental gene control at both transcriptional and post-transcriptional levels.

Marta Murcia, PhD

The New York Academy of Sciences


Stefan Ameres
Stefan Ameres, PhD

University of Massachusetts Medical School
e-mail | web site | publications

Stefan Ameres studied biology at Friedrich-Alexander University Erlangen–Nuremberg, Germany. He did his PhD at the Max F. Perutz Laboratories in Vienna, Austria where he studied the molecular basis for target RNA recognition by small RNAs in the laboratory of Renée Schroeder. Now, Ameres works as a postdoc with Phillip Zamore at the University of Massachusetts Medical School, where he studies regulatory aspects of RNA silencing pathways in Drosophila and mammals.

Weifeng Gu, PhD

University of Massachusetts Medical School
email | web site | publications

Weifeng Gu received his MD from Peking University Health Science Center (previously known as Beijing Medical University), where he studied human chemokines. He did his PhD at University of Rochester with Eric Phizicky studying tRNA modification. Then he went to UMass Medical school to work with Craig Mello as a postdoc to study endogenous small RNAs in C. elegans.

Nelson Lau

Nelson Lau, PhD

Brandeis University
e-mail | web site | publications

Nelson Lau is an assistant professor of biology at Brandeis University, and his laboratory studies gene and genome regulatory processes controlled by small RNAs. Lau obtained a PhD from MIT where he worked with David Bartel, and hewas a Whitney Foundation Fellow in Robert Kingston's lab at Massachusetts General Hospital, where he discovered piRNAs from rats and mice. Lau is a 2010 Searle Scholar and a recipient of an NIH K99 award.

Haifan Lin

Haifan Lin, PhD

Yale University School of Medicine
e-mail | web site | publications

Haifan Lin is Professor of Cell Biology and Director of the Yale Stem Cell Center at the Yale University School of Medicine. Lin's research has greatly strengthened understanding of the molecular mechanisms that define the unique behavior of stem cells. His early contributions include identification of stem cells in the Drosophila ovary and establishment of these stem cells as an effective model for study. Lin has discovered key genes involved in both niche signaling and intracellular regulation, most notably the piwi/argonaute gene family. His work on Piwi proteins lead to the discovery of a group of small RNAs called PIWI-interacting, or piRNAs. The discovery of piRNAs independently by Lin and others was recognized by Science Magazine as a top scientific breakthrough of 2006. Currently, the Lin lab is exploring the role of these molecules in epigenetic and posttranscriptional regulation of gene expression.

Zissimos Mourelatos

Zissimos Mourelatos, MD

University of Pennsylvania, School of Medicine
e-mail | web site | publications

Zissimos Mourelatos obtained his MD from the Aristotelian University, Greece in 1991. From 1991 to 1995 he was research fellow in the laboratory of Nicholas Gonatas at PENN, studying the cell biology of the Golgi apparatus in neurons and in motor neuron diseases. From 1995 to 1998 he was resident in Anatomic Pathology and clinical fellow in Neuropathology. From 1998 to 2002 he was postdoctoral fellow in the laboratory of Gideon Dreyfuss at PENN. Since 2002 he is a faculty member of the Department of Pathology & Laboratory Medicine at PENN. His laboratory investigates the basic biology of small regulatory RNPs and also how RNA dysregulation contributes to neurodegeneration. He is also a practicing surgical neuropathologist and the director of Neuropathology at PENN.

Priya Rajasethupathy

Priya Rajasethupathy

Columbia University
email | web site

Priya Rajasethupathy attended Cornell University for her undergraduate studies, and majored in Biological Sciences. She received her BA degree and graduated Suma Cum Laude from Cornell in 2004. She then traveled to India and spent one year as a research student at the National Center for Biological Sciences in Bangalore, India. Upon returning, she joined the MD–PhD program at Columbia University, where she is currently pursuing her PhD in neuroscience with Eric Kandel.

Haruhiko Siomi

Haruhiko Siomi, PhD

Keio University School of Medicine
e-mail | web site | publications

Haruhiko Siomi has obtained his Diploma degree (1982) and MS degree (1984) in Chemistry ('sugar chemistry') at Gifu University, and his PhD (1988) in virology ('HTLV1') at the Institute for Virus Research in Kyoto University. He joined the Gideon Dreyfuss laboratory in the Department of Biochemistry and Biophysics at the University of Pennsylvania School of Medicine as a HHMI associate in May 1990 and later promoted to Research Assistant Professor ('hnRNPs and FMR1'). In 1999, he became a Professor in the Institute for Genome Research at the University of Tokushima. He then moved to Keio University School of Medicine as Professor in Department of Molecular Biology in 2008. His laboratory investigates various aspects of RNA silencing.

Zev Williams

Zev Williams, MD

The Rockefeller University
e-mail | web site | publications

Zev Williams is a research associate in the laboratory of Dr. Thomas Tuschl at Rockefeller University and a senior fellow in reproductive endocrinology and infertility at Weill–Cornell Medical Center. He received his MD and PhD degrees from the Mount Sinai School of Medicine with Dr. Paul Wassarman where he studied the biosynthesis and assembly of the mammalian egg coat. He continued his studies on the molecular biology of the oocyte through his residency in Obstetrics and Gynecology at the Brigham and Women's Hospital and Massachusetts General Hospital.

Keith Mulvihill

Keith Mulvihill is a freelance writer based in Manhattan. He worked as an environmental chemist before becoming a science writer. He covers a wide range of topics and has contributed to a variety of newspapers, magazines and websites.