Activation of transposable elements during aging and neuronal decline in Drosophila

Li, Wanhe; Prazak, Lisa; Chatterjee, Nabanita; Grüninger, Servan; Krug, Lisa; Theodorou, Delphine; Dubnau, Josh

doi:10.1038/nn.3368

Cited by 292 publications

(416 citation statements)

References 25 publications

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“…The endogenous siRNA pathway mediated by Dicer‐2 ( Dcr‐2 ) and Argonaute2 ( AGO2 ) have been shown to repress retrotransposon expression in Drosophila somatic cells. Previous studies have shown that AGO2 mutant flies or shRNA‐mediated depletion of AGO2 caused increased expression of retrotransposons in Drosophila brain and S2 cells (Czech et al ., 2008; Ghildiyal et al ., 2008; Li et al ., 2013). Thus, we depleted AGO2 in the fat body ( Cg‐gal4>AGO2 shRNA) by shRNA (mediated by Dicer‐1 ‐ AGO1 ) using two different fly RNAi lines (line 1: Bloomington Stock Center #34799, and line 2: Bloomington Stock Center #55672) that target different AGO2 sequences.…”

Section: Resultsmentioning

confidence: 99%

“…Studies of the old Drosophila brains have also revealed an increased expression of several TEs, including the gypsy retrotransposon (Li et al ., 2013). More recent studies have reported increased expression of Alu retrotransposons in the retinal pigmented epithelial cells from old humans, which can contribute to age‐associated macular degeneration (Kaneko et al ., 2011; Tarallo et al ., 2012).…”

Section: Introductionmentioning

confidence: 99%

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Age‐associated de‐repression of retrotransposons in the Drosophila fat body, its potential cause and consequence

et al. 2016

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SummaryEukaryotic genomes contain transposable elements (TE) that can move into new locations upon activation. Since uncontrolled transposition of TEs, including the retrotransposons and DNA transposons, can lead to DNA breaks and genomic instability, multiple mechanisms, including heterochromatin‐mediated repression, have evolved to repress TE activation. Studies in model organisms have shown that TEs become activated upon aging as a result of age‐associated deregulation of heterochromatin. Considering that different organisms or cell types may undergo distinct heterochromatin changes upon aging, it is important to identify pathways that lead to TE activation in specific tissues and cell types. Through deep sequencing of isolated RNAs, we report an increased expression of many retrotransposons in the old Drosophila fat body, an organ equivalent to the mammalian liver and adipose tissue. This de‐repression correlates with an increased number of DNA damage foci and decreased level of Drosophila lamin‐B in the old fat body cells. Depletion of the Drosophila lamin‐B in the young or larval fat body results in a reduction of heterochromatin and a corresponding increase in retrotransposon expression and DNA damage. Further manipulations of lamin‐B and retrotransposon expression suggest a role of the nuclear lamina in maintaining the genome integrity of the Drosophila fat body by repressing retrotransposons.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Age‐associated de‐repression of retrotransposons in the Drosophila fat body, its potential cause and consequence

et al. 2016

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“…Earlier studies found that LINE1 can actively retrotranspose in Drosophila, mouse, and human brain (9,11,41). The LINE1 promoter is active in neural precursor cells differentiating into neurons (9,42).…”

Section: Discussionmentioning

confidence: 99%

Roles for small noncoding RNAs in silencing of retrotransposons in the mammalian brain

Nandi

Chandramohan

Fioriti

et al. 2016

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

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Piwi-interacting RNAs (piRNAs), long thought to be restricted to germline, have recently been discovered in neurons of Aplysia, with a role in the epigenetic regulation of gene expression underlying long-term memory. We here ask whether piwi/piRNAs are also expressed and have functional roles in the mammalian brain. Large-scale RNA sequencing and subsequent analysis of protein expression revealed the presence in brain of several piRNA biogenesis factors including a mouse piwi (Mili), as well as small RNAs, albeit at low levels, resembling conserved piRNAs in mouse testes [primarily LINE1 (long interspersed nuclear element1) retrotransposon-derived]. Despite the seeming low expression of these putative piRNAs, single-base pair CpG methylation analyses across the genome of Mili/piRNA-deficient (Mili −/− ) mice demonstrate that brain genomic DNA is preferentially hypomethylated within intergenic areas and LINE1 promoter areas of the genome. Furthermore, Mili mutant mice exhibit behavioral deficits such as hyperactivity and reduced anxiety. These results suggest that putative piRNAs exist in mammalian brain, and similar to the role of piRNAs in testes, they may be involved in the silencing of retrotransposons, which in brain have critical roles in contributing to genomic heterogeneity underlying adaptation, stress response, and brain pathology. We also describe the presence of another class of small RNAs in the brain, with features of endogenous siRNAs, which may have taken over the role of invertebrate piRNAs in their capacity to target both transposons, as well as protein-coding genes. Thus, RNA interference through gene and retrotransposon silencing previously encountered in Aplysia may also have potential roles in the mammalian brain.piwi-interacting RNA | transposon | DNA methylation | behavior | endogenous siRNA P iwi-interacting RNAs (piRNAs) are 26-to 32-nt small noncoding RNAs that associate with the piwi clade of the Argonaute family of proteins and whose primary functions in mammals are associated with the silencing of transposons in the germline through de novo DNA methylation (1-4). Transposons constitute 44% of the human genome and could when active contribute to genetic heterogeneity, to alteration of behavior during adaptation, and to responses to stress. Somatic retrotransposition and its associated insertional mutagenesis have particularly important implications for brain disorders and are often associated with schizophrenia, Rett syndrome, and neurodegenerative disorders (5-7). The LINE1 (long interspersed nuclear element1) family of retrotransposons in particular is active in human and mouse hippocampus (8, 9).Although it has long been thought that piRNA expression and function are restricted to the germline, our laboratory and others have previously found that the piRNA pathway is functional in invertebrate neurons as well (10, 11). Aplysia neurons, in particular, have a strikingly abundant expression of piRNAs (contributing to at least 5% of the total noncoding RNA population); they in turn hav...

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“…Small numbers of transposable element genes, mostly retroposons, and pseudo-genes were both up-and down-regulated during leaf senescence. This contrasts to animal cells, where a general increase in expression and mobility of transposable element genes has been observed in older somatic cells (De Cecco et al, 2013;Li et al, 2013a). A gene ontology (GO) analysis was performed on this list of SURGs and SDRGs, and enriched biological processes with false discovery rates below 1% are shown in Table I.…”

Section: Rna-seq Gene Expression Analysismentioning

confidence: 99%

A Genome-Wide Chronological Study of Gene Expression and Two Histone Modifications, H3K4me3 and H3K9ac, during Developmental Leaf Senescence

et al. 2015

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The genome-wide abundance of two histone modifications, H3K4me3 and H3K9ac (both associated with actively expressed genes), was monitored in Arabidopsis (Arabidopsis thaliana) leaves at different time points during developmental senescence along with expression in the form of RNA sequencing data. H3K9ac and H3K4me3 marks were highly convergent at all stages of leaf aging, but H3K4me3 marks covered nearly 2 times the gene area as H3K9ac marks. Genes with the greatest fold change in expression displayed the largest positively correlated percentage change in coverage for both marks. Most senescence up-regulated genes were premarked by H3K4me3 and H3K9ac but at levels below the whole-genome average, and for these genes, gene expression increased without a significant increase in either histone mark. However, for a subset of genes showing increased or decreased expression, the respective gain or loss of H3K4me3 marks was found to closely match the temporal changes in mRNA abundance; 22% of genes that increased expression during senescence showed accompanying changes in H3K4me3 modification, and they include numerous regulatory genes, which may act as primary response genes.

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Activation of transposable elements during aging and neuronal decline in Drosophila

Cited by 292 publications

References 25 publications

Age‐associated de‐repression of retrotransposons in the Drosophila fat body, its potential cause and consequence

Age‐associated de‐repression of retrotransposons in the Drosophila fat body, its potential cause and consequence

Roles for small noncoding RNAs in silencing of retrotransposons in the mammalian brain

A Genome-Wide Chronological Study of Gene Expression and Two Histone Modifications, H3K4me3 and H3K9ac, during Developmental Leaf Senescence

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