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Regulatory RNAs and control of epigenetic mechanisms: expectations for cognition and cognitive dysfunction

    Anderson A Butler

    Department of Neurobiology, University of Alabama at Birmingham, 1825 University Boulevard, Birmingham, AL 35294, USA

    ,
    William M Webb

    Department of Neurobiology, University of Alabama at Birmingham, 1825 University Boulevard, Birmingham, AL 35294, USA

    &
    Farah D Lubin

    *Author for correspondence:

    E-mail Address: flubin@uab.edu

    Department of Neurobiology, University of Alabama at Birmingham, 1825 University Boulevard, Birmingham, AL 35294, USA

    Published Online:https://doi.org/10.2217/epi.15.79

    The diverse functions of noncoding RNAs (ncRNAs) can influence virtually every aspect of the transcriptional process including epigenetic regulation of genes. In the CNS, regulatory RNA networks and epigenetic mechanisms have broad relevance to gene transcription changes involved in long-term memory formation and cognition. Thus, it is becoming increasingly clear that multiple classes of ncRNAs impact neuronal development, neuroplasticity, and cognition. Currently, a large gap exists in our knowledge of how ncRNAs facilitate epigenetic processes, and how this phenomenon affects cognitive function. In this review, we discuss recent findings highlighting a provocative role for ncRNAs including lncRNAs and piRNAs in the control of epigenetic mechanisms involved in cognitive function. Furthermore, we discuss the putative roles for these ncRNAs in cognitive disorders such as schizophrenia and Alzheimer's disease.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1 Bonasio R, Tu S, Reinberg D. Molecular signals of epigenetic states. Science 330, 612–616 (2010).
    • 2 Gan Q, Yoshida T, McDonald OG, Owens GK. Concise review: epigenetic mechanisms contribute to pluripotency and cell lineage determination of embryonic stem cells. Stem Cells 25, 2–9 (2007).
    • 3 Hemberger M, Dean W, Reik W. Epigenetic dynamics of stem cells and cell lineage commitment: digging Waddington's canal. Nat. Rev. Mol. Cell Biol. 10, 526–537 (2009).
    • 4 Maze I, Noh K-M, Allis CD. Histone regulation in the CNS: basic principles of epigenetic plasticity. Neuropsychopharmacology 38(1), 3–22 (2013).
    • 5 Juliandi B, Abematsu M, Nakashima K. Epigenetic regulation in neural stem cell differentiation. Dev. Growth Differ. 52, 493–504 (2010).
    • 6 Yu Y, Casaccia P, Richard Lu Q. Shaping the oligodendrocyte identity by epigenetic control. Epigenetics 5, 124–128 (2010).
    • 7 Rudenko A, Tsai L-H. Epigenetic modifications in the nervous system and their impact upon cognitive impairments. Neuropharmacology 80(2014), 70–82 (2014).
    • 8 Lubin FD, Gupta S, Parrish RR, Grissom NM, Davis RL. Epigenetic mechanisms: critical contributors to long-term memory formation. Neuroscientist 17(6), 616–632 (2011).
    • 9 Network P. Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways. Nat. Neurosci. 18(2), 199–209 (2015).
    • 10 Gupta-Agarwal S, Franklin AV, DeRamus T et al. G9a/GLP histone lysine dimethyltransferase complex activity in the hippocampus and the entorhinal cortex is required for gene activation and silencing during memory consolidation. J. Neurosci. 32, 5440–5453 (2012).
    • 11 Jarome TJ, Lubin FD. Epigenetic mechanisms of memory formation and reconsolidation. Neurobiol. Learn. Mem. 115, 116–127 (2014).•• Reviews the considerable body of work on the epigenetics of memory consolidation and reconsolidation. As memory is one of the best studied cognitive phenomenon, this provides an introduction to the wide scope of epigenetic mechanisms in cognition.
    • 12 Liang J, Wan M, Zhang Y et al. Nanog and Oct4 associate with unique transcriptional repression complexes in embryonic stem cells. Nat. Cell Biol. 10(6), 731–739 (2008).
    • 13 Vento-Tormo R, Rodriguez-Ubreva J, Lisio LD et al. NF-ĸB directly mediates epigenetic deregulation of common microRNAs in Epstein–Barr virus-mediated transformation of B-cells and in lymphomas. Nucleic Acids Res. 42(17), 11025–11039 (2014).
    • 14 Zhong H, May MJ, Jimi E, Ghosh S. The phosphorylation status of nuclear NF-ĸB determines its association with CBP/p300 or HDAC-1. Mol. Cell. 9(3), 625–636 (2002).
    • 15 Harrow J, Denoeud F, Frankish A et al. GENCODE: producing a reference annotation for ENCODE. Genome Biol. 7(Suppl. 1), S4.1–9 (2006).
    • 16 Ravasi T, Suzuki H, Pang KC et al. Experimental validation of the regulated expression of large numbers of non-coding RNAs from the mouse genome. Genome Res. 16, 11–19 (2006).
    • 17 Mercer T, Mercer T, Dinger M et al. Specific expression of long noncoding RNAs in the mouse brain. Proc. Natl Acad. Sci. USA 105, 716–721 (2008).
    • 18 Lunnon K, Smith R, Hannon E et al. Methylomic profiling implicates cortical deregulation of ANK1 in Alzheimer's disease. Nat. Neurosci. 17(9), 1164–1170 (2014).
    • 19 Harrow J, Frankish A, Gonzalez JM et al. GENCODE: the reference human genome annotation for the ENCODE project. Genome Res. 22, 1760–1774 (2012).
    • 20 Candeias MM, Malbert-Colas L, Powell DJ et al. P53 mRNA controls p53 activity by managing Mdm2 functions. Nat. Cell Biol. 10(9), 1098–1105 (2008).
    • 21 Gajjar M, Candeias MM, Malbert-Colas L et al. The p53 mRNA-Mdm2 interaction controls Mdm2 nuclear trafficking and is required for p53 activation following dna damage. Cancer Cell 21(1), 25–35 (2012).
    • 22 Naski N, Gajjar M, Bourougaa K, Malbert-Colas L, Fåhraeus R, Candeias MM. The p53 mRNA-Mdm2 interaction. Cell Cycle 8(1), 31–34 (2009).
    • 23 Mattick JS, Rinn JL. Discovery and annotation of long noncoding RNAs. Nat. Publ. Gr. 22(1), 5–7 (2015).• This recent review provides a thorough review of lncRNA discovery and annotation, described by two of the most prominent RNA biologists involved.
    • 24 Cam HP. Roles of RNAi in chromatin regulation and epigenetic inheritance. Epigenomics 2, 613–626 (2010).• This review discusses the RNAi pathway as it relates to heterochromatin assembly – and therefore, transcriptional regulation – in yeast.
    • 25 Schaukowitch K, Kim T-K. Emerging epigenetic mechanisms of long non-coding RNAs. Neuroscience 264, 25–38 (2014).
    • 26 Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75(5), 843–854 (1993).
    • 27 Lagos-Quintana M, Rauhut R, Lendeckel W, Tuschl T. Identification of novel genes coding for small expressed RNAs. Science 294(5543), 853–858 (2001).
    • 28 Lewis BP, Burge CB, Bartel DP. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120(1), 15–20 (2005).
    • 29 Friedman RC, Farh KKH, Burge CB, Bartel DP. Most mammalian mRNAs are conserved targets of microRNAs. Genome Res. 19(1), 92–105 (2009).
    • 30 Griffiths-Jones S. The microRNA Registry. Nucleic Acids Res. 32, D109–D111 (2004).
    • 31 Griffiths-Jones S, Grocock RJ, van Dongen S, Bateman A, Enright AJ. miRBase: microRNA sequences, targets and gene nomenclature. Nucleic Acids Res. 34, D140–D144 (2006).
    • 32 Griffiths-Jones S, Saini HK, Van Dongen S, Enright AJ. miRBase: tools for microRNA genomics. Nucleic Acids Res. 36(Suppl. 1), D154–D158 (2008).
    • 33 Kozomara A, Griffiths-Jones S. MiRBase: integrating microRNA annotation and deep-sequencing data. Nucleic Acids Res. 39(Suppl. 1), D152–D157 (2011).
    • 34 Kozomara A, Griffiths-Jones S. MiRBase: annotating high confidence microRNAs using deep sequencing data. Nucleic Acids Res. 42(D1), D68–D73 (2014).
    • 35 Leonardo TR, Schultheisz HL, Loring JF, Laurent LC. The functions of microRNAs in pluripotency and reprogramming. Nat. Cell Biol. 14(11), 1114–1121 (2012).
    • 36 Ichimura A, Ruike Y, Terasawa K, Tsujimoto G. miRNAs and regulation of cell signaling. FEBS J. 278(10), 1610–1618 (2011).
    • 37 Ono K, Kuwabara Y, Han J. MicroRNAs and cardiovascular diseases. FEBS J. 278(10), 1619–1633 (2011).
    • 38 Lu J, Getz G, Miska EA et al. MicroRNA expression profiles classify human cancers. Nature 435(7043), 834–838 (2005).
    • 39 Fernandez-Valverde SL, Taft RJ, Mattick JS. MicroRNAs in β-cell biology, insulin resistance, diabetes and its complications. Diabetes 60(7), 1825–1831 (2011).
    • 40 Bredy TW, Lin Q, Wei W, Baker-Andresen D, Mattick JS. MicroRNA regulation of neural plasticity and memory. Neurobiol. Learn. Mem. 96(1), 89–94 (2011).
    • 41 Park CY, Choi YS, McManus MT. Analysis of microRNA knockouts in mice. Hum. Mol. Genet. 19(R2), R169–R175 (2010).
    • 42 Krol J, Loedige I, Filipowicz W. The widespread regulation of microRNA biogenesis, function and decay. Nat. Rev. Genet. 11(9), 597–610 (2010).
    • 43 Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116(2), 281–297 (2004).
    • 44 Pillai RS, Bhattacharyya SN, Filipowicz W. Repression of protein synthesis by miRNAs: how many mechanisms? Trends Cell Biol. 17(3), 118–126 (2007).
    • 45 Barry G. Integrating the roles of long and small non-coding RNA in brain function and disease. Mol. Psychiatry 19(4), 410–416 (2014).
    • 46 Kocerha J, Dwivedi Y, Brennand KJ. Noncoding RNAs and neurobehavioral mechanisms in psychiatric disease. Mol. Psychiatry 20(6), 677–684 (2015).
    • 47 De Pietri Tonelli D, Pulvers JN, Haffner C, Murchison EP, Hannon GJ, Huttner WB. miRNAs are essential for survival and differentiation of newborn neurons but not for expansion of neural progenitors during early neurogenesis in the mouse embryonic neocortex. Development 135(23), 3911–3921 (2008).
    • 48 Huang T, Liu Y, Huang M, Zhao X, Cheng L. Wnt1-cre-mediated conditional loss of Dicer results in malformation of the midbrain and cerebellum and failure of neural crest and dopaminergic differentiation in mice. J. Mol. Cell Biol. 2(3), 152–163 (2010).
    • 49 Kawase-Koga Y, Low R, Otaegi G et al. RNAase-III enzyme Dicer maintains signaling pathways for differentiation and survival in mouse cortical neural stem cells. J. Cell Sci. 123(Pt 4), 586–594 (2010).
    • 50 Hébert SS, Papadopoulou AS, Smith P et al. Genetic ablation of Dicer in adult forebrain neurons results in abnormal tau hyperphosphorylation and neurodegeneration. Hum. Mol. Genet. 19(20), 3959–3969 (2010).
    • 51 Davis TH, Cuellar TL, Koch SM et al. Conditional loss of Dicer disrupts cellular and tissue morphogenesis in the cortex and hippocampus. J. Neurosci. 28(17), 4322–4330 (2008).
    • 52 Konopka W, Kiryk A, Novak M et al. MicroRNA loss enhances learning and memory in mice. J. Neurosci. 30(44), 14835–14842 (2010).
    • 53 Wu P, Zuo X, Deng H, Liu X, Liu L, Ji A. Roles of long noncoding RNAs in brain development, functional diversification and neurodegenerative diseases. Brain Res. Bull. 97, 69–80 (2013).
    • 54 Liu T, Huang Y, Chen J et al. Attenuated ability of BACE1 to cleave the amyloid precursor protein via silencing long noncoding RNA BACE1-AS expression. Mol. Med. Rep. 10(3), 1275–1281 (2014).
    • 55 Spadaro PA, Flavell CR, Widagdo J et al. Long noncoding RNA-directed epigenetic regulation of gene expression is associated with anxiety-like behavior in mice. Biol. Psychiatry doi:10.1016/j.biopsych.2015.02.004 (2015) (Epub ahead of print).• Demonstrates lncRNA-mediated epigenetic disruptions accompanied by a perturbed cognitive state.
    • 56 Kryger R, Fan L, Wilce PA, Jaquet V. MALAT–1, a non protein-coding RNA is upregulated in the cerebellum, hippocampus and brain stem of human alcoholics. Alcohol 46(7), 629–634 (2012).
    • 57 Fenoglio C, Ridolfi E, Galimberti D, Scarpini E. An emerging role for long non-coding RNA dysregulation in neurological disorders. Int. J. Mol. Sci. 14(10), 20427–20442 (2013).
    • 58 Smalheiser NR, Lugli G, Zhang H, Rizavi H, Cook EH, Dwivedi Y. Expression of micrornas and other small RNAs in prefrontal cortex in schizophrenia, bipolar disorder and depressed subjects. PLoS ONE 9(1), 1–12 (2014).
    • 59 Cao M-Q, Chen D-H, Zhang C-H, Wu Z-Z. [Screening of specific microRNA in hippocampus of depression model rats and intervention effect of Chaihu Shugan San]. Zhongguo Zhong Yao Za Zhi 38(10), 1585–1589 (2013).
    • 60 Miller BH, Zeier Z, Xi L et al. MicroRNA-132 dysregulation in schizophrenia has implications for both neurodevelopment and adult brain function. Proc. Natl Acad. Sci. 109(8), 3125–3130 (2012).
    • 61 Li YJ, Xu M, Gao ZH et al. Alterations of serum levels of BDNF-related miRNAs in patients with depression. PLoS ONE 8(5), 1–7 (2013).
    • 62 Sun G, Ye P, Murai K et al. miR-137 forms a regulatory loop with nuclear receptor TLX and LSD1 in neural stem cells. Nat. Commun. 2, 529 (2011).
    • 63 Guo A-Y, Sun J, Jia P, Zhao Z. A novel microRNA and transcription factor mediated regulatory network in schizophrenia. BMC Syst. Biol. 4, 10 (2010).
    • 64 Tognini P, Putignano E, Coatti A, Pizzorusso T. Experience-dependent expression of miR-132 regulates ocular dominance plasticity. Nat. Neurosci. 14(10), 1237–1239 (2011).
    • 65 Lei X, Lei L, Zhang Z, Zhang Z, Cheng Y. Downregulated miR-29c correlates with increased BACE1 expression in sporadic Alzheimer's disease. Int. J. Clin. Exp. Pathol. 8(2), 1565–1574 (2015).
    • 66 Stark KL, Xu B, Bagchi A et al. Altered brain microRNA biogenesis contributes to phenotypic deficits in a 22q11-deletion mouse model. Nat. Genet. 40(6), 751–760 (2008).
    • 67 Kocerha J, Faghihi MA, Lopez-Toledano MA et al. MicroRNA-219 modulates NMDA receptor-mediated neurobehavioral dysfunction. Proc. Natl Acad. Sci. USA 106(9), 3507–3512 (2009).
    • 68 Moreau MP, Bruse SE, David-Rus R, Buyske S, Brzustowicz LM. Altered MicroRNA expression profiles in postmortem brain samples from individuals with schizophrenia and bipolar disorder. Biol. Psychiatry 69(2), 188–193 (2011).
    • 69 Santarelli DM, Beveridge NJ, Tooney PA, Cairns MJ. Upregulation of Dicer and MicroRNA expression in the dorsolateral prefrontal cortex Brodmann area 46 in schizophrenia. Biol. Psychiatry 69(2), 180–187 (2011).
    • 70 Mellios N, Huang HS, Grigorenko A, Rogaev E, Akbarian S. A set of differentially expressed miRNAs, including miR-30a-5p, act as post-transcriptional inhibitors of BDNF in prefrontal cortex. Hum. Mol. Genet. 17(19), 3030–3042 (2008).
    • 71 Beveridge NJ, Gardiner E, Carroll AP, Tooney PA, Cairns MJ. Schizophrenia is associated with an increase in cortical microRNA biogenesis. Mol. Psychiatry 15(12), 1176–1189 (2010).
    • 72 Dugas JC, Cuellar TL, Scholze A et al. Dicer1 and miR-219 are required for normal oligodendrocyte differentiation and myelination. Neuron 65(5), 597–611 (2010).
    • 73 Moser JJ, Fritzler MJ. The microRNA and messengerRNA profile of the RNA-induced silencing complex in human primary astrocyte and astrocytoma cells. PLoS ONE 5(10), e13445 (2010).
    • 74 Mor E, Cabilly Y, Goldshmit Y et al. Species-specific microRNA roles elucidated following astrocyte activation. Nucleic Acids Res. 39(9), 3710–3723 (2011).
    • 75 Numakawa T, Yamamoto N, Chiba S et al. Growth factors stimulate expression of neuronal and glial miR-132. Neurosci. Lett. 505(3), 242–247 (2011).
    • 76 Li Z, Yang C-S, Nakashima K, Rana TM. Small RNA-mediated regulation of iPS cell generation. EMBO J. 30(5), 823–834 (2011).
    • 77 Zhang S, Hao J, Xie F et al. Downregulation of miR-132 by promoter methylation contributes to pancreatic cancer development. Carcinogenesis 32(8), 1183–1189 (2011).
    • 78 Grayson DR, Guidotti A. The dynamics of DNA methylation in schizophrenia and related psychiatric disorders. Neuropsychopharmacology 38(1), 138–166 (2013).
    • 79 Ripke S, Sanders AR, Kendler KS et al. Genome-wide association study identifies five new schizophrenia loci. Nat. Genet. 43(10), 969–976 (2011).
    • 80 Akbarian S. Epigenetics of schizophrenia. Curr. Top. Behav. Neurosci. 2010(4), 611–628 (2010).
    • 81 Szulwach KE, Li X, Smrt RD et al. Cross talk between microRNA and epigenetic regulation in adult neurogenesis. J. Cell Biol. 189(1), 127–141 (2010).
    • 82 Hamilton AJ. A species of small antisense RNA in posttranscriptional gene silencing in plants. Science 286(5441), 950–952 (1999).
    • 83 Valencia-Sanchez MA, Liu J, Hannon GJ, Parker R. Control of translation and mRNA degradation by miRNAs and siRNAs. Genes Dev. 20(5), 515–524 (2006).
    • 84 Chen L, Dahlstrom JE, Lee SH, Rangasamy D. Naturally occurring endo-siRNA silences LINE–1 retrotransposons in human cells through DNA methylation. Epigenetics 7(7), 758–771 (2012).
    • 85 Palanichamy JK, Mehndiratta M, Bhagat M et al. Silencing of integrated human papillomavirus–16 oncogenes by small interfering RNA-mediated heterochromatization. Mol. Cancer Ther. 9(7), 2114–2122 (2010).
    • 86 Verdel A, Vavasseur A, Le Gorrec M, Touat-Todeschini L. Common themes in siRNA-mediated epigenetic silencing pathways. Int. J. Dev. Biol. 53(2–3), 245–257 (2009).
    • 87 Matzke MA, Mosher RA. RNA-directed DNA methylation: an epigenetic pathway of increasing complexity. Nat. Rev. Genet. 15(6), 394–408 (2014).
    • 88 Ye R, Wang W, Iki T et al. Cytoplasmic Assembly and selective nuclear import of arabidopsis ARGONAUTE4/siRNA complexes. Mol. Cell. 46(6), 859–870 (2012).
    • 89 Wierzbicki AT, Haag JR, Pikaard CS. Noncoding transcription by RNA polymerase Pol IVb/Pol V mediates transcriptional silencing of overlapping and adjacent genes. Cell 135(4), 635–648 (2008).
    • 90 He XJ, Hsu YF, Pontes O et al. NRPD4, a protein related to the RPB4 subunit of RNA polymerase II, is a component of RNA polymerases IV and v and is required for RNA-directed DNA methylation. Genes Dev. 23(3), 318–330 (2009).
    • 91 Gao Z, Liu H-L, Daxinger L et al. An RNA polymerase II- and AGO4-associated protein acts in RNA-directed DNA methylation. Nature 465(7294), 106–109 (2010).
    • 92 Zhong X, Du J, Hale CJ et al. Molecular mechanism of action of plant DRM de novo DNA methyltransferases. Cell 157(5), 1050–1060 (2014).
    • 93 Aliya N, Rahman S, Khan ZK, Jain P. Cotranscriptional chromatin remodeling by small RNA species: an HTLV-1perspective. Leuk. Res. Treatment 2012, 1–15 (2012).
    • 94 Li LC. Chromatin remodeling by the small rna machinery in mammalian cells. Epigenetics 9(1), 45–52 (2014).
    • 95 Toscano-Garibay JD, Aquino-Jarquin G. Transcriptional regulation mechanism mediated by miRNA-DNA•DNA triplexstructure stabilized by Argonaute. Biochim. Biophys. Acta. 1839(11), 1079–1083 (2014).
    • 96 Tam OH, Aravin AA, Stein P et al. Pseudogene-derived small interfering RNAs regulate gene expression in mouse oocytes. Nature 453(7194), 534–538 (2008).
    • 97 Watanabe T, Totoki Y, Toyoda A et al. Endogenous siRNAs from naturally formed dsRNAs regulate transcripts in mouse oocytes. Nature 453(7194), 539–543 (2008).
    • 98 Maida Y, Yasukawa M, Okamoto N et al. Involvement of telomerase reverse transcriptase in heterochromatin maintenance. Mol. Cell. Biol. 34(9), 1576–1593 (2014).
    • 99 Babiarz JE, Ruby JG, Wang Y, Bartel DP, Blelloch R. Mouse ES cells express endogenous shRNAs, siRNAs, and other microprocessor-independent, Dicer-dependent small RNAs. Genes Dev. 22(20), 2773–2785 (2008).
    • 100 Castellano L, Stebbing J. Deep sequencing of small RNAs identifies canonical and non-canonical miRNA and endogenous siRNAs in mammalian somatic tissues. Nucleic Acids Res. 41(5), 3339–3351 (2013).
    • 101 Smalheiser NR. The search for endogenous siRNAs in the mammalian brain. Exp. Neurol. 235(2), 455–463 (2012).
    • 102 Smalheiser NR, Lugli G, Thimmapuram J, Cook EH, Larson J. Endogenous siRNAs and noncoding RNA-derived small RNAs are expressed in adult mouse hippocampus and are up-regulated in olfactory discrimination training. RNA 17(1), 166–181 (2011).
    • 103 Le Thomas A, Tóth KF, Aravin AA. To be or not to be a piRNA: genomic origin and processing of piRNAs. Genome Biol. 15(1), 204 (2014).
    • 104 Han BW, Zamore PD. piRNAs. Curr. Biol. 24(16), R730–R733 (2014).
    • 105 Kuramochi-Miyagawa S, Kimura T, Ijiri TW et al. Mili, a mammalian member of PIWI family gene, is essential for spermatogenesis. Development 131(4), 839–849 (2004).
    • 106 Lin H, Spradling AC. A novel group of pumilio mutations affects the asymmetric division of germline stem cells in the Drosophila ovary. Development 124(12), 2463–2476 (1997).
    • 107 Cox DN, Chao A, Baker J, Chang L, Qiao D, Lin H. A novel class of evolutionarily conserved genes defined by PIWI are essential for stem cell self-renewal. Genes Dev. 12(23), 3715–3727 (1998).
    • 108 Grimaud C, Bantignies F, Pal-Bhadra M, Ghana P, Bhadra U, Cavalli G. RNAi components are required for nuclear clustering of polycomb group response elements. Cell 124(5), 957–971 (2006).
    • 109 Girard A, Sachidanandam R, Hannon GJ, Carmell MA. A germline-specific class of small RNAs binds mammalian PIWI proteins. Nature 442(7099), 199–202 (2006).
    • 110 Robine N, Lau NC, Balla S et al. A broadly conserved pathway generates 3′UTR-directed primary piRNAs. Curr. Biol. 19(24), 2066–2076 (2009).
    • 111 Rajasethupathy P, Antonov I, Sheridan R et al. A role for neuronal piRNAs in the epigenetic control of memory-related synaptic plasticity. Cell 149, 693–707 (2012).• This study is among the first evidence of neuroepigenetic regulation in memory-related neuronal activity by piRNAs, and drives the expectation that future studies will uncover piRNA-mediated neurocognitive mechanisms.
    • 112 Ross RJ, Weiner MM, Lin H. PIWI proteins and PIWI-interacting RNAs in the soma. Nature 505(7483), 353–359 (2014).
    • 113 Brower-Toland B, Findley SD, Jiang L et al. Drosophila PIWI associates with chromatin and interacts directly with HP1a. Genes Dev. 21(18), 2300–2311 (2007).
    • 114 Piacentini L, Fanti L, Negri R et al. Heterochromatin Protein 1 (HP1a) positively regulates euchromatic gene expression through RNA transcript association and interaction with hnRNPs in Drosophila. PLoS Genet. 5(10), e1000670 (2009).
    • 115 Yin H, Lin H. An epigenetic activation role of PIWI and a PIWI-associated piRNA in Drosophila melanogaster. Nature 450(7167), 304–308 (2007).
    • 116 Carmell MA, Girard A, van de Kant HJG et al. MIWI2 is essential for spermatogenesis and repression of transposons in the mouse male germline. Dev. Cell. 12(4), 503–514 (2007).
    • 117 Aravin AA, Sachidanandam R, Bourc'his D et al. A piRNA pathway primed by individual transposons is linked to de novo DNA methylation in mice. Mol. Cell. 31(6), 785–799 (2008).
    • 118 Kuramochi-Miyagawa S, Watanabe T, Gotoh K et al. DNA methylation of retrotransposon genes is regulated by PIWI family members MILI and MIWI2 in murine fetal testes. Genes Dev. 22(7), 908–917 (2008).
    • 119 Lee EJ, Banerjee S, Zhou H et al. Identification of piRNAs in the central nervous system. RNA 17(6), 1090–1099 (2011).
    • 120 Wright MW. A short guide to long non-coding RNA gene nomenclature. Hum. Genomics 8, 7 (2014).
    • 121 Tsai M-C, Manor O, Wan Y et al. Long noncoding RNA as modular scaffold of histone modification complexes. Science 329, 689–693 (2010).
    • 122 Guttman M, Rinn JL. Modular regulatory principles of large non-coding RNAs. Nature 482, 339–346 (2012).
    • 123 Pachnis V, Brannan CI, Tilghman SM. The structure and expression of a novel gene activated in early mouse embryogenesis. EMBO J. 7, 673–681 (1988).
    • 124 Sanli K, Karlsson FH, Nookaew I, Nielsen J. FANTOM: functional and taxonomic analysis of metagenomes. BMC Bioinformatics 14, 38 (2013).
    • 125 Pauli A, Valen E, Lin MF et al. Systematic identification of long noncoding RNAs expressed during zebrafish embryogenesis. Genome Res. 22, 577–591 (2012).
    • 126 Cabili M, Trapnell C, Goff L et al. Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses. Genes Dev. 25, 1915–1927 (2011).
    • 127 Mercer TR, Clark MB, Crawford J et al. Targeted sequencing for gene discovery and quantification using RNA CaptureSeq. Nat. Protoc. 9, 989–1009 (2014).
    • 128 Mercer TR, Gerhardt DJ, Dinger ME et al. Targeted RNA sequencing reveals the deep complexity of the human transcriptome. Nat. Biotechnol. 30, 99–104 (2011).
    • 129 Fu GK, Xu W, Wilhelmy J et al. Molecular indexing enables quantitative targeted RNA sequencing and reveals poor efficiencies in standard library preparations. Proc. Natl Acad. Sci. USA 111, 1891–1896 (2014).
    • 130 Morris K V. Long antisense non-coding RNAs function to direct epigenetic complexes that regulate transcription in human cells. Epigenetics 4, 296–301 (2009).
    • 131 Klevebring D, Bjursell M, Emanuelsson O, Lundeberg J. In-depth transcriptome analysis reveals novel TARs and prevalent antisense transcription in human cell lines. PLoS ONE 5(3), e9762 (2010).
    • 132 Katayama S, Tomaru Y, Kasukawa T et al. Antisense transcription in the mammalian transcriptome. Science 309, 1564–1566 (2005).
    • 133 Pelechano V, Steinmetz LM. Gene regulation by antisense transcription. Nat. Rev. Genet. 14, 880–893 (2013).
    • 134 Morris K V, Mattick JS. The rise of regulatory RNA. Nat. Rev. Genet. 15, 423–437 (2014).•• This excellent review discusses the history of RNA and describes many important mechanisms of regulatory NA function.
    • 135 Chew G-L, Pauli A, Rinn JL, Regev A, Schier AF, Valen E. Ribosome profiling reveals resemblance between long non-coding RNAs and 5 leaders of coding RNAs. Development 140, 2828–2834 (2013).
    • 136 Guttman M, Russell P, Ingolia NT, Weissman JS, Lander ES. Ribosome profiling provides evidence that large noncoding RNAs do not encode proteins. Cell 154(1), 240–251 (2013).
    • 137 Ingolia NT, Brar GA, Stern-Ginossar N et al. Ribosome profiling reveals pervasive translation outside of annotated protein-coding genes. Cell Rep. 8(5), 1365–1379 (2014).
    • 138 Zhang B, Arun G, Mao YS et al. The lncRNA malat1 is dispensable for mouse development but its transcription plays a cis-regulatory role in the adult. Cell Rep. 2, 111–123 (2012).
    • 139 Modarresi F, Faghihi MA, Lopez-Toledano M A et al. Inhibition of natural antisense transcripts in vivo results in gene-specific transcriptional upregulation. Nat. Biotechnol. 30(5), 453–459 (2012).
    • 140 Jiao AL, Slack FJ. RNA-mediated gene activation. Epigenetics 9, 27–36 (2014).
    • 141 Schaukowitch K, Kim T-K. Emerging epigenetic mechanisms of long non-coding RNAs. Neuroscience 264, 25–38 (2014).
    • 142 Zappulla DC, Cech TR. RNA as a flexible scaffold for proteins: yeast telomerase and beyond. Cold Spring Harb. Symp. Quant. Biol. 71, 217–224 (2006).
    • 143 Froberg JE, Yang L, Lee JT. Guided by RNAs: X-inactivation as a model for lncRNA function. J. Mol. Biol. 425, 3698–3706 (2013).
    • 144 Di Ruscio A, Ebralidze AK, Benoukraf T et al. DNMT1-interacting RNAs block gene-specific DNA methylation. Nature 503(7476), 371–376 (2013).
    • 145 Kornienko AE, Guenzl PM, Barlow DP, Pauler FM. Gene regulation by the act of long non-coding RNA transcription. BMC Biol. 11, 59 (2013).
    • 146 He S, Zhang H, Liu H, Zhu H. LongTarget: a tool to predict lncRNA DNA-binding motifs and binding sites via Hoogsteen base-pairing analysis. Bioinformatics 31(2), 178–186 (2014).
    • 147 Li X, Kazan H, Lipshitz HD, Morris QD. Finding the target sites of RNA-binding proteins. Wiley Interdiscip. Rev. RNA 5, 111–130 (2014).
    • 148 Li X, Quon G, Lipshitz HD, Morris Q. Predicting in vivo binding sites of RNA-binding proteins using mRNA secondary structure. RNA 16, 1096–1107 (2010).
    • 149 Gerstberger S, Hafner M, Tuschl T. A census of human RNA-binding proteins. Nat. Rev. Genet. 15(12), 829–845 (2014).
    • 150 Kartha RV, Subramanian S. Competing endogenous RNAs (ceRNAs): new entrants to the intricacies of gene regulation. Front. Genet. 5, 8 (2014).
    • 151 Bosia C, Pagnani A, Zecchina R. Modeling competing endogenous RNAs networks. Arxiv Prepr. Arxiv 1210, 2336 (2012).
    • 152 Jalali S, Bhartiya D, Lalwani MK, Sivasubbu S, Scaria V. Systematic transcriptome wide analysis of lncRNA-miRNA interactions. PLoS ONE 8 (2013).
    • 153 Nakagawa S, Kageyama Y. Nuclear lncRNAs as epigenetic regulators-beyond skepticism. Biochim. Biophys. Acta 1839, 215–222 (2014).
    • 154 Khalil AM, Guttman M, Huarte M et al. Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proc. Natl Acad. Sci. USA 106, 11667–11672 (2009).• Up to 20% of lncRNAs are shown to bind to the PRC2, a chromatin-modifying complex with known activity in the CNS.
    • 155 Zhao T, Xu J, Liu L et al. Computational identification of epigenetically regulated lncRNAs and their associated genes based on integrating genomic data. FEBS Lett. 589(4), 521–531 (2015).
    • 156 Petazzi P, Sandoval J, Szczesna K et al. Dysregulation of the long non-coding RNA transcriptome in a Rett syndrome mouse model. RNA Biol. 10, 1197–1203 (2013).
    • 157 Ziats MN, Rennert OM. Aberrant expression of long noncoding RNAs in autistic brain. J. Mol. Neurosci. 49, 589–593 (2013).
    • 158 Lipovich L, Dachet F, Cai J et al. Activity-dependent human brain coding/noncoding gene regulatory networks. Genetics 192(3), 1133–1148 (2012).
    • 159 Sauvageau M, Goff LA, Lodato S et al. Multiple knockout mouse models reveal lncRNAs are required for life and brain development. Elife 2013(2), e01749 (2013).
    • 160 Bernard D, Prasanth K V, Tripathi V et al. A long nuclear-retained non-coding RNA regulates synaptogenesis by modulating gene expression. EMBO J. 29(18), 3082–3093 (2010).
    • 161 West JA, Davis Cp, Sunwoo H et al. The long noncoding RNAs NEAT1 and MALAT1 bind active chromatin sites. Mol. Cell. 55(5), 791–802 (2014).
    • 162 Guil S, Soler M, Portela A et al. Intronic RNAs mediate EZH2 regulation of epigenetic targets. Nat. Struct. Mol. Biol. 19(7), 664–670 (2012).• Describes a role for noncoding, intronic RNA in controlling gene transcription via the PRC2 This complex containing the methyltransferase activity of its EZH2 subunit is known to influence hippocampal neurogenesis and memory formation.
    • 163 Eißmann M, Gutschner T, Hämmerle M et al. Loss of the abundant nuclear non-coding RNA MALAT1 is compatible with life and development. RNA Biol. 9(8), 1076–1087 (2012).
    • 164 Barry G, Briggs J, Vanichkina D. The long non-coding RNA Gomafu is acutely regulated in response to neuronal activation and involved in schizophrenia-associated alternative splicing. Mol. Psychiatry 19(4), 486–494 (2013).
    • 165 Stilling RM, Fischer A. The role of histone acetylation in age-associated memory impairment and Alzheimer's disease. Neurobiol. Learn. Mem. 96, 19–26 (2011).
    • 166 Lu X, Deng Y, Yu D et al. Histone acetyltransferase p300 mediates histone acetylation of PS1 and BACE1 in a cellular model of Alzheimer's disease. PLoS ONE 9(7), 1–9 (2014).
    • 167 Sathya M, Premkumar P, Karthick C, Moorthi P, Jayachandran KS, Anusuyadevi M. BACE1 in Alzheimer's disease. Clin. Chim. Acta 414, 171–178 (2012).
    • 168 Faghihi MA, Zhang M, Huang J et al. Evidence for natural antisense transcript-mediated inhibition of microRNA function. Genome Biol. 11(5), R56 (2010).
    • 169 Modarresi F, Faghihi MA, Patel NS, Sahagan BG, Wahlestedt C, Lopez-Toledano MA. Knockdown of BACE1-AS nonprotein-coding transcript modulates beta-amyloid-related hippocampal neurogenesis. Int. J. Alzheimers. Dis. 2011, 929042 (2011).
    • 170 Morgan HD, Santos F, Green K, Dean W, Reik W. Epigenetic reprogramming in mammals. Hum. Mol. Genet. 14(1), R47–R58 (2005).
    • 171 Carone BR, Fauquier L, Habib N et al. Paternally induced transgenerational environmental reprogramming of metabolic gene expression in mammals. Cell 143(7), 1084–1096 (2010).
    • 172 Dias BG, Ressler KJ. Parental olfactory experience influences behavior and neural structure in subsequent generations. Nat. Neurosci. 17(1), 89–96 (2014).
    • 173 Gapp K, Jawaid A, Sarkies P et al. Implication of sperm RNAs in transgenerational inheritance of the effects of early trauma in mice. Nat. Neurosci. 17(5), 667–669 (2014).
    • 174 Pembrey ME, Bygren LO, Kaati G et al. Sex-specific, male-line transgenerational responses in humans. Eur. J. Hum. Genet. 14(2), 159–166 (2006).
    • 175 Skinner MK, Mohan M, Haque MM, Zhang B, Savenkova MI. Epigenetic transgenerational inheritance of somatic transcriptomes and epigenetic control regions. Genome Biol. 13(10), R91 (2012).
    • 176 Migicovsky Z, Kovalchuk I. Epigenetic memory in mammals. Front. Genet. 2, 28 (2011).
    • 177 Yuan S, Oliver D, Schuster A, Zheng H, Yan W. Breeding scheme and maternal small RNAs affect the efficiency of transgenerational inheritance of a paramutation in mice. Sci. Rep. 5, 9266 (2015).
    • 178 Devanapally S, Ravikumar S, Jose AM. Double-stranded RNA made in C. elegans neurons can enter the germline and cause transgenerational gene silencing. Proc. Natl Acad. Sci. USA 112(7), 2133–2138 (2015).