Abstract
Classically thought as genomic clutter, the functional significance of transposable elements (TEs) has only recently become a focus of attention in neuroscience. Increasingly, studies have demonstrated that the brain seems to have more retrotransposition and TE transcription relative to other somatic tissues, suggesting a unique role for TEs in the central nervous system. TE expression and transposition also appear to vary by brain region and change in response to environmental stimuli such as stress. TEs appear to serve a number of adaptive roles in the nervous system. The regulation of TE expression by steroid, epigenetic and other mechanisms in interplay with the environment represents a significant and novel avenue to understanding both normal brain function and disease.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1 . Chromosome organization and genic expression. Cold Spring Harb. Symp. Quant. Biol. 16, 13–47 (1951). • The first description of transposons and their activity.
- 2 . The significance of responses of the genome to challenge. Science 226(4676), 792–801 (1984). • Proposes that transposable elements (TEs) influence gene expression in response to environmental stressors.
- 3 . Selfish DNA: the ultimate parasite. Nature 284(5757), 604–607 (1980).
- 4 . So much ‘junk’ DNA in our genome. Brookhaven Symp. Biol. 23, 366–370 (1972).
- 5 The ENCODE (ENCyclopedia Of DNA Elements) Project. Science 306(5696), 636–640 (2004).
- 6 Deep transcriptome profiling of mammalian stem cells supports a regulatory role for retrotransposons in pluripotency maintenance. Nat. Genet. 46(6), 558–566 (2014).
- 7 DICER1 loss and Alu RNA induce age-related macular degeneration via the NLRP3 inflammasome and MyD88. Cell 149(4), 847–859 (2012).
- 8 . InvAluable junk: the cellular impact and function of Alu and B2 RNAs. IUBMB Life 61(8), 831–837 (2009).
- 9 . Haemophilia A resulting from de novo insertion of L1 sequences represents a novel mechanism for mutation in man. Nature 332(6160), 164–166 (1988).
- 10 . The role of transposable elements in health and diseases of the central nervous system. J. Neurosci. 33(45), 17577–17586 (2013).
- 11 . Repbase update, a database of eukaryotic repetitive elements. Cytogenet. Genome Res. 110(1–4), 462–467 (2005).
- 12 . Dynamic interactions between transposable elements and their hosts. Nat. Rev. Genet. 12(9), 615–627 (2011).
- 13 A unified classification system for eukaryotic transposable elements. Nat. Rev. Genet. 8(12), 973–982 (2007).
- 14 Initial sequencing and analysis of the human genome. Nature 409(6822), 860–921 (2001).
- 15 . Retrotransposons revisited: the restraint and rehabilitation of parasites. Cell 135(1), 23–35 (2008).
- 16 . Reverse transcriptase encoded by a human transposable element. Science 254(5039), 1808–1810 (1991).
- 17 . Ribonucleoprotein particle formation is necessary but not sufficient for LINE-1 retrotransposition. Hum. Mol. Genet. 14(21), 3237–3248 (2005).
- 18 L1 retrotransposition in nondividing and primary human somatic cells. Proc. Natl Acad. Sci. USA 103(21), 8036–8041 (2006).
- 19 . Cell divisions are required for L1 retrotransposition. Mol. Cell Biol. 27(4), 1264–1270 (2007).
- 20 L1 retrotransposition in human neural progenitor cells. Nature 460(7259), 1127–1131 (2009).
- 21 L1 retrotransposition occurs mainly in embryogenesis and creates somatic mosaicism. Genes Dev. 23(11), 1303–1312 (2009).
- 22 . Somatic mosaicism in neuronal precursor cells mediated by L1 retrotransposition. Nature 435(7044), 903–910 (2005). • First study demonstrating L1 retrotransposition in the brain.
- 23 The regulated retrotransposon transcriptome of mammalian cells. Nat. Genet. 41(5), 563–571 (2009). • First study demonstrating L1 retrotransposition in the brain.
- 24 . Mobile elements in the human genome: implications for disease. Genome Med. 4(2), 12 (2012).
- 25 . RNA truncation by premature polyadenylation attenuates human mobile element activity. Nat. Genet. 35(4), 363–366 (2003).
- 26 . The APOBEC3 cytidine deaminases: an innate defensive network opposing exogenous retroviruses and endogenous retroelements. Annu. Rev. Immunol. 26, 317–353 (2008).
- 27 High-molecular-mass APOBEC3G complexes restrict Alu retrotransposition. Proc. Natl Acad. Sci. USA 103(42), 15588–15593 (2006).
- 28 . RNA interference, transposon silencing, and cosuppression in the caenorhabditis elegans germ line: similarities and differences. Cold Spring Harb. Symp. Quant. Biol. 69, 397–402 (2004).
- 29 Discrete small RNA-generating loci as master regulators of transposon activity in Drosophila. Cell 128(6), 1089–1103 (2007).
- 30 . LINE-1 ORF1 protein localizes in stress granules with other RNA-binding proteins, including components of RNA interference RNA-induced silencing complex. Mol. Cell. Biol. 27(18), 6469–6483 (2007).
- 31 . McClintock's challenge in the 21st century. Proc. Natl Acad. Sci. USA 109(50), 20200–20203 (2012).
- 32 . Is most of our DNA garbage! The New York Times Magazine March 8th (2015).
- 33 . Exon shuffling by L1 retrotransposition. Science 283(5407), 1530–1534 (1999).
- 34 . Mobile elements: drivers of genome evolution. Science 303(5664), 1626–1632 (2004). • Elegant explanation of the important role of TEs in driving genome evolution.
- 35 . The distribution of L1 and Alu retroelements in relation to GC content on human sex chromosomes is consistent with the ectopic recombination model. J. Mol. Evol. 63(4), 484–492 (2006).
- 36 . Stress and the dynamic genome: steroids, epigenetics, and the transposome. Proc. Natl Acad. Sci. USA 112(22), 6828–6833 (2014).
- 37 . An siRNA pathway prevents transgenerational retrotransposition in plants subjected to stress. Nature 472(7341), 115–119 (2011).
- 38 . Presidential address. Transposable elements, epigenetics, and genome evolution. Science 338(6108), 758–767 (2012).
- 39 . Transposable elements and genome organization: a comprehensive survey of retrotransposons revealed by the complete Saccharomyces cerevisiae genome sequence. Genome Res. 8(5), 464–478 (1998).
- 40 Potential impact of stress activated retrotransposons on genome evolution in a marine diatom. BMC Genomics 10, 624 (2009).
- 41 . Transposable elements and factors influencing their success in eukaryotes. J. Hered. 100(5), 648–655 (2009).
- 42 . The paleontology of intergene retrotransposons of maize. Nat. Genet. 20(1), 43–45 (1998).
- 43 . Mobile DNA elements in the generation of diversity and complexity in the brain. Nat. Rev. Neurosci. 15(8), 497–506 (2014).
- 44 . RAG1 core and V(D)J recombination signal sequences were derived from Transib transposons. PLoS Biol. 3(6), e181 (2005).
- 45 . What makes each brain unique. Sci. Am. 306(3), 26–31 (2012).
- 46 . Hypomethylation marks enhancers within transposable elements. Nat. Genet. 45(7), 717–718 (2013).
- 47 . Expression pattern of the Nijmegen breakage syndrome gene, Nbs1, during murine development. Hum. Mol. Genet. 9(12), 1739–1744 (2000).
- 48 A human genome structural variation sequencing resource reveals insights into mutational mechanisms. Cell 143(5), 837–847 (2010).
- 49 . The Masterpiece of Nature: The Evolution and Genetics of Sexuality. University of California Press, CA, USA (1982).
- 50 . Transposable elements: an abundant and natural source of regulatory sequences for host genes. Annu. Rev. Genet. 46, 21–42 (2012).
- 51 . Altruistic functions for selfish DNA. Cell cycle 8(18), 2895–2900 (2009).
- 52 . Evolution of the repertoire of nuclear receptor binding sites in genomes. Mol. Cell. Endocrinol. 334(1–2), 76–82 (2011).
- 53 Suv39h-dependent H3K9me3 marks intact retrotransposons and silences LINE elements in mouse embryonic stem cells. Mol. Cell 55(2), 277–290 (2014).
- 54 A transcription factor-based mechanism for mouse heterochromatin formation. Nat. Struct. Mol. Biol. 19(10), 1023–1030 (2012).
- 55 . Keeping active endogenous retroviral-like elements in check: the epigenetic perspective. Cell. Mol. Life Sci. 65(21), 3329–3347 (2008).
- 56 GENCODE: the reference human genome annotation for The ENCODE Project. Genome Res. 22(9), 1760–1774 (2012).
- 57 Defining functional DNA elements in the human genome. Proc. Natl Acad. Sci. USA 111(17), 6131–6138 (2014).
- 58 . Transposable elements reveal a stem cell-specific class of long noncoding RNAs. Genome Biol. 13(11), R107 (2012).
- 59 Transposable elements are major contributors to the origin, diversification, and regulation of vertebrate long noncoding RNAs. PLoS Genet. 9(4), e1003470 (2013).
- 60 Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses. Genes Dev. 25(18), 1915–1927 (2011).
- 61 Somatic retrotransposition alters the genetic landscape of the human brain. Nature 479(7374), 534–537 (2011).
- 62 Transposition-driven genomic heterogeneity in the Drosophila brain. Science 340(6128), 91–95 (2013).
- 63 Increased l1 retrotransposition in the neuronal genome in schizophrenia. Neuron 81(2), 306–313 (2014).
- 64 Single-neuron sequencing analysis of L1 retrotransposition and somatic mutation in the human brain. Cell 151(3), 483–496 (2012). •• Provides a lower bound for L1 insertion rate in the brain.
- 65 Ubiquitous L1 mosaicism in hippocampal neurons. Cell 161(2), 228–239 (2015).
- 66 The evidence for increased L1 activity in the site of human adult brain neurogenesis. PLoS ONE 10(2), e0117854 (2015). •• Provides an upper bound for L1 insertion rate in the mammalian hippocampus.
- 67 . Environmental influence on L1 retrotransposons in the adult hippocampus. Hippocampus 19(10), 1002–1007 (2009).
- 68 . High-throughput sequencing reveals extensive variation in human-specific L1 content in individual human genomes. Genome Res. 20(9), 1262–1270 (2010).
- 69 . The SINE-encoded mouse B2 RNA represses mRNA transcription in response to heat shock. Nat. Struct. Mol. Biol. 11(9), 816–821 (2004).
- 70 Human Alu RNA is a modular transacting repressor of mRNA transcription during heat shock. Mol. Cell 29(4), 499–509 (2008).
- 71 . Amygdala transcriptome and cellular mechanisms underlying stress-enhanced fear learning in a rat model of posttraumatic stress disorder. Neuropsychopharmacology 35(6), 1402–1411 (2010).
- 72 . Gene coexpression networks in human brain identify epigenetic modifications in alcohol dependence. J. Neurosci. 32(5), 1884–1897 (2012).
- 73 Acute stress and hippocampal histone H3 lysine 9 trimethylation, a retrotransposon silencing response. Proc. Natl Acad. Sci. USA 109(43), 17657–17662 (2012). • Demonstrates silencing of TE expression in the hippocampus in response to acute environmental stress through histone methylation.
- 74 . Cocaine dynamically regulates heterochromatin and repetitive element unsilencing in nucleus accumbens. Proc. Natl Acad. Sci. USA 108(7), 3035–3040 (2011).
- 75 Wnt-mediated activation of NeuroD1 and retro-elements during adult neurogenesis. Nat. Neurosci. 12(9), 1097–1105 (2009).
- 76 L1 retrotransposition in neurons is modulated by MeCP2. Nature 468(7322), 443–446 (2010).
- 77 . Silencing of endogenous retroviruses: when and why do histone marks predominate? Trends Biochem. Sci. 37(4), 127–133 (2012).
- 78 . Active human retrotransposons: variation and disease. Curr. Opin. Genet. Dev. 22(3), 191–203 (2012).
- 79 Activation of transposable elements during aging and neuronal decline in Drosophila. Nat. Neurosci. 16(5), 529–531 (2013).
- 80 . Estimating enrichment of repetitive elements from high-throughput sequence data. Genome Biol. 11(6), R69 (2010).
- 81 . SetDB1 contributes to repression of genes encoding developmental regulators and maintenance of ES cell state. Genes Dev. 23(21), 2484–2489 (2009).
- 82 DNA methylation and SETDB1/H3K9me3 regulate predominantly distinct sets of genes, retroelements, and chimeric transcripts in mESCs. Cell stem cell 8(6), 676–687 (2011).
- 83 hnRNP K coordinates transcriptional silencing by SETDB1 in embryonic stem cells. PLoS Genet. 11(1), e1004933 (2015).
- 84 Setdb1 is required for germline development and silencing of H3K9me3-marked endogenous retroviruses in primordial germ cells. Genes Dev. 28(18), 2041–2055 (2014).
- 85 KAP1 controls endogenous retroviruses in embryonic stem cells. Nature 463(7278), 237–240 (2010).
- 86 TRIM28 represses transcription of endogenous retroviruses in neural progenitor cells. Cell Rep. 10(1), 20–28 (2015).
- 87 Plzf mediates transcriptional repression of HoxD gene expression through chromatin remodeling. Dev. Cell 3(4), 499–510 (2002).
- 88 Histone acetyltransferase activity of p300 is required for transcriptional repression by the promyelocytic leukemia zinc finger protein. Mol. Cell. Biol. 25(13), 5552–5566 (2005).
- 89 RARalpha-PLZF overcomes PLZF-mediated repression of CRABPI, contributing to retinoid resistance in t(11;17) acute promyelocytic leukemia. Proc. Natl Acad. Sci. USA 104(47), 18694–18699 (2007).
- 90 The epigenetic regulator PLZF represses L1 retrotransposition in germ and progenitor cells. EMBO J. 32(13), 1941–1952 (2013).
- 91 . Stress induces atrophy of apical dendrites of hippocampal CA3 pyramidal neurons. Brain Res. 588(2), 341–345 (1992).
- 92 . Stress and anxiety across the lifespan: structural plasticity and epigenetic regulation. Epigenomics 5(2), 177–194 (2013).
- 93 . Physiology and neurobiology of stress and adaptation: central role of the brain. Physiol. Rev. 87(3), 873–904 (2007).
- 94 . Hippocampal gene expression changes underlying stress sensitization and recovery. Mol. Psychiatry 19(11), 1171–1178 (2014).
- 95 . Neuroepigenetics of stress. Neuroscience 275, 420–435 (2014).
- 96 . Epigenetic effects of stress and corticosteroids in the brain. Front. Cell. Neurosci. 6, 18 (2012).
- 97 . Regulation of hippocampal H3 histone methylation by acute and chronic stress. Proc. Natl Acad. Sci. USA 106(49), 20912–20917 (2009).
- 98 . Environmental stress and transposon transcription in the mammalian brain. Mob. Genet. Elements 3(2), e24555 (2013).
- 99 . Characterization of the structure, function, and mechanism of B2 RNA, an ncRNA repressor of RNA polymerase II transcription. RNA 13(4), 583–596 (2007).
- 100 . B2 RNA binds directly to RNA polymerase II to repress transcript synthesis. Nat. Struct. Mol. Biol. 11(9), 822–829 (2004).
- 101 . Protein synthesis and memory: a review. Psychol. Bull. 96(3), 518–559 (1984).
- 102 . ALU repeats in promoters are position-dependent co-response elements (coRE) that enhance or repress transcription by dimeric and monomeric progesterone receptors. Mol. Endocrinol. 23(7), 989–1000 (2009).
- 103 . Exaptation of an ancient Alu short interspersed element provides a highly conserved vitamin D-mediated innate immune response in humans and primates. BMC Genomics 10, 321 (2009).
- 104 Nuclear receptor-induced chromosomal proximity and DNA breaks underlie specific translocations in cancer. Cell 139(6), 1069–1083 (2009).
- 105 . Aberrant chromosomes: not so random after all? J. Natl Cancer Inst. 102(6), 368–369 (2010).
- 106 . From ancestral infectious retroviruses to bona fide cellular genes: role of the captured syncytins in placentation. Placenta 33(9), 663–671 (2012).
- 107 Tissue-specific high-level expression of human endogenous retrovirus-R in the human adrenal cortex. Pathobiology 66(5), 209–215 (1998).
- 108 . PIWI-interacting small RNAs: the vanguard of genome defence. Nat. Rev. Mol. Cell Biol. 12(4), 246–258 (2011).
- 109 . Epidemiological trends in rates of autism. Mol. Psychiatry 7(Suppl. 2), S4–S6 (2002).
- 110 . Transposable elements in TDP-43-mediated neurodegenerative disorders. PLoS ONE 7(9), e44099 (2012).
- 111 . The relationship of adverse childhood experiences to adult medical disease, psychiatric disorders and sexual behavior: implications for healthcare. In: The Impact Of Early Life Trauma On Health And Disease: The Hidden Epidemic.. Lanius RA, Vermetten E, Pain C (Eds). Cambridge University Press, Cambridge, New York, USA, xvii, 315 (2010).
- 112 . Childhood adversity and combat as predictors of depression and post-traumatic stress in deployed troops. Am. J. Prev. Med. 33(2), 77–82 (2007).
- 113 DNA methylation in repetitive elements and post-traumatic stress disorder: a case-control study of US military service members. Epigenomics 4(1), 29–40 (2012).
- 114 Magnetic resonance imaging-based measurement of hippocampal volume in posttraumatic stress disorder related to childhood physical and sexual abuse – a preliminary report. Biol. Psychiatry 41(1), 23–32 (1997).
- 115 Smaller hippocampal volume in patients with recent-onset posttraumatic stress disorder. Biol. Psychiatry 56(11), 832–836 (2004).
- 116 . To poly(I:C) or not to poly(I:C): advancing preclinical schizophrenia research through the use of prenatal immune activation models. Neuropharmacology 62(3), 1308–1321 (2012).
- 117 . Cytokine and growth factor involvement in schizophrenia–support for the developmental model. Mol. Psychiatry 5(6), 594–603 (2000).
- 118 . In utero infection and adult schizphrenia. Ment. Retard. Dev. Disabil. Res. Rev. 8, 51–57 (2002).
- 119 Excessive extracellular volume reveals a neurodegenerative pattern in schizophrenia onset. J. Neurosci. 32(48), 17365–17372 (2012).
- 120 . ‘The missing genes: what happened to the heritability of psychiatric disorders?’ Mol. Psychiatry 16(4), 362–364 (2011).
- 121 . Retroviruses and amyotrophic lateral sclerosis. Antiviral Res. 99(2), 180–187 (2013).