piRNAs, transposon silencing, and germline genome integrity

Castaneda, Julio M; Genzor, Pavol; Bortvin, Alex

doi:10.1016/j.mrfmmm.2011.05.002

Cited by 93 publications

(71 citation statements)

References 159 publications

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“…This histone modification reflects a prominent mechanism of piRNA-mediated repression and is generally associated with silenced genes (for review, see Malone and Hannon 2009;Castaneda et al 2011;Holoch and Moazed 2015). Consistent with this, H3K9me3 marks were clearly enriched at the L1 enhancer region of wildtype embryos injected with the LRE3 reporter ( Fig.…”

Section: P53 Limits Retrotransposition In Fishsupporting

confidence: 65%

p53 genes function to restrain mobile elements

et al. 2015

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Throughout the animal kingdom, p53 genes govern stress response networks by specifying adaptive transcriptional responses. The human member of this gene family is mutated in most cancers, but precisely how p53 functions to mediate tumor suppression is not well understood. Using Drosophila and zebrafish models, we show that p53 restricts retrotransposon activity and genetically interacts with components of the piRNA (piwi-interacting RNA) pathway. Furthermore, transposon eruptions occurring in the p53 − germline were incited by meiotic recombination, and transcripts produced from these mobile elements accumulated in the germ plasm. In gene complementation studies, normal human p53 alleles suppressed transposons, but mutant p53 alleles from cancer patients could not. Consistent with these observations, we also found patterns of unrestrained retrotransposons in p53-driven mouse and human cancers. Furthermore, p53 status correlated with repressive chromatin marks in the 5 ′ sequence of a synthetic LINE-1 element. Together, these observations indicate that ancestral functions of p53 operate through conserved mechanisms to contain retrotransposons. Since human p53 mutants are disabled for this activity, our findings raise the possibility that p53 mitigates oncogenic disease in part by restricting transposon mobility.

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Section: P53 Limits Retrotransposition In Fishsupporting

confidence: 65%

p53 genes function to restrain mobile elements

et al. 2015

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“…The presence of unpaired DNA regions during meiosis triggers epigenetic marking by DNA methylation, which subsequently leads to elimination of the insert (20). In mammals there is evidence that genes unpaired during pachytene are subject to postmeiotic transcriptional repression (21), and it is well established that both plants and animals, including mammals, have evolved elaborate mechanisms to silence TEs (22)(23)(24)(25)(26)(27). We thus assume that vertebrates recognize and epigenetically mark insertions.…”

Section: Significancementioning

confidence: 99%

Enhanced evolution by stochastically variable modification of epigenetic marks in the early embryo

Branciamore

Rodin

Riggs

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Evolution by gene duplication is generally accepted as one of the crucial driving forces for the gain of new complexity and functions, but the formation of pseudogenes remains a problem for this mechanism. Here we expand on earlier ideas that epigenetic modifications can drive neo-and subfunctionalization in evolution by gene duplication. We explore the effects of stochastic epigenetic modifications on the evolution (and thus development) of complex organisms in a constant environment. Modeling is done both using a modified genetic drift analytical treatment and computer simulations, which were found to agree. A transposon silencing model is also explored. Some key assumptions made include (i) stochastic, incomplete removal (or addition) of repressive epigenetic marks takes place during a window(s) of opportunity in the zygote and early embryo; (ii) there is no statistical variation of the marks after the window closes; and (iii) the genes affected are sensitive to dosage. Our genetic drift treatment takes into account that after gene duplication the prevailing case upon which selection operates is a duplicate/singlet heterozygote; to the best of our knowledge, this has not been considered in previous treatments. We conclude from our modeling that stochastic epigenetic modifications, with rates consistent with experimental observation, can both increase the rate of gene fixation and decrease pseudogenization, thus dramatically improving the efficacy of evolution by gene duplication. We also find that a transposon silencing model is advantageous for fixation of recessive genes in diploid organisms, especially with large effective population sizes.DNA methylation | mathematical modeling | computational biology | molecular evolution | developmental biology O ne of the crucial driving forces behind gaining new complexity and functions in the evolutionary process is evolution by gene duplication, an idea that was first proposed and substantiated in the seminal work of Susumu Ohno (1). Due to technological progress in whole genome sequencing and omics in general, we recently have gained a much better qualitative and quantitative understanding of the extent and patterns of gene duplication in extant genomes. However, the actual evolutionary dynamics of gene duplication events are still a matter of considerable debate. Though the molecular underpinnings of generating duplicate gene copies are well understood, it is during the subsequent fixation of gene duplicates that a serious difficulty arises-namely, how to avoid pseudogenization, which is statistically much more likely than new or diversified functions.Substantial biological evidence, as well as theoretical considerations, suggests that epigenetic events influence not only development of individual organisms but also evolutionary processes (2-7). For example, epigenetic silencing by DNA methylation, which is generally a repressive mark, has the potential for tissue-specific gene silencing and thus, as we and others have reported (8-10), may greatly accelerate the r...

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“…CLIP-seq has shown that miRNAs bind preferentially to the 3 ′ untranslated region (UTR) and coding sequence (CDS) of protein-coding genes (Chi et al 2009;Hafner et al 2010;Zisoulis et al 2010). Piwi proteins are expressed primarily in the germline, bind piRNAs and use them to target and silence transposons (Seto et al 2007;Klattenhoff and Theurkauf 2008;Ghildiyal and Zamore 2009;Senti and Brennecke 2010;Castaneda et al 2011;Siomi et al 2011;Ishizu et al 2012;Pillai and Chuma 2012;Guzzardo et al 2013;Weick and Miska 2014). CLIP-seq for Piwi proteins revealed that they may also bind directly to long RNAs without using piRNAs as guides, either in the process of piRNA biogenesis or to bind to mRNAs (Vourekas et al 2012(Vourekas et al , 2015.…”

Section: Introductionmentioning

confidence: 99%

CLIPSeqTools—a novel bioinformatics CLIP-seq analysis suite

Maragkakis

Alexiou

Nakaya

et al. 2015

RNA

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Immunoprecipitation of RNA binding proteins (RBPs) after in vivo crosslinking, coupled with sequencing of associated RNA footprints (HITS-CLIP, CLIP-seq), is a method of choice for the identification of RNA targets and binding sites for RBPs. Compared with RNA-seq, CLIP-seq analysis is widely diverse and depending on the RBPs that are analyzed, the approaches vary significantly, necessitating the development of flexible and efficient informatics tools. In this study, we present CLIPSeqTools, a novel, highly flexible computational suite that can perform analysis from raw sequencing data with minimal user input. It contains a wide array of tools to provide an in-depth view of CLIP-seq data sets. It supports extensive customization and promotes improvization, a critical virtue, since CLIP-seq analysis is rarely well defined a priori. To highlight CLIPSeqTools capabilities, we used the suite to analyze Ago-miRNA HITS-CLIP data sets that we prepared from human brains.

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piRNAs, transposon silencing, and germline genome integrity

Cited by 93 publications

References 159 publications

p53 genes function to restrain mobile elements

p53 genes function to restrain mobile elements

Enhanced evolution by stochastically variable modification of epigenetic marks in the early embryo

CLIPSeqTools—a novel bioinformatics CLIP-seq analysis suite

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