CHAPTER SEVEN

MicroRNAs and Ethanol Toxicity Rajesh C. Miranda1 Department of Neuroscience and Experimental Therapeutics and Women’s Health in Neuroscience Program, A&M Health Science Center, College of Medicine, Bryan, Texas, USA 1 Corresponding author: e-mail address: [email protected]

Contents 1. Introduction 2. miRNAs and Their Biogenesis 2.1 Biogenesis of miRNAs 3. Mechanisms of miRNA Function 3.1 Targeting 30 UTRs for mRNA degradation and translation repression 3.2 Alternate functions of miRNAs 4. miRNAs as Mediators of Ethanol Effects in Developing and Adult Tissues 4.1 miR-9: An example of a common developmental and adult ethanol target 4.2 Ethanol and epigenetic control over miRNA expression 4.3 Ethanol-sensitive miRNAs as mediators of epigenetic control 5. miRNA-Mediated Transgenerational Inheritance of Information: A Novel Mechanism for Transgenerational Transfer of Epimutations? 6. Conclusions Acknowledgments References

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Abstract MicroRNAs (miRNAs) are a class of small nonprotein-coding RNAs (ncRNAs) that have been shown to promote the degradation of target messenger RNAs and inhibit the translation of networks of protein-coding genes to control the development of cells and tissues, and facilitate their adaptation to environmental forces. In this chapter, we will discuss recent data that show that miRNAs are an important component of the epigenetic landscape that regulates the transcription as well as the translation of protein-coding gene networks. We will discuss the evidence that implicates miRNAs in both developmental and adult effects of alcohol consumption. Understanding the interactions of this novel class of ncRNAs with the epigenome will be important for understanding the etiology of alcohol teratology and addiction as well as potential new treatment strategies.

International Review of Neurobiology, Volume 115 ISSN 0074-7742 http://dx.doi.org/10.1016/B978-0-12-801311-3.00007-X

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1. INTRODUCTION Ethyl alcohol (alcohol or ethanol), though widely consumed, is a drug with significant abuse potential, organ toxicity, and teratogenicity. Alcohol consumption is associated with the development of phenomena like tolerance, dependence, and alcohol cessation-associated withdrawal effects, indicating that alcohol has addictive potential (Koob & Volkow, 2010). Alcohol affects the function of, and is toxic to, many organ systems including the nervous (Harper, 2009), cardiovascular (Laonigro, Correale, Di Biase, & Altomare, 2009), hepatic and immune (Miller, Horiguchi, Jeong, Radaeva, & Gao, 2011), and skeletal (Maurel, Boisseau, Benhamou, & Jaffre, 2012) systems. Alcohol consumption is associated with digestive tract and liver (Haas, Ye, & Lohr, 2012) and breast (Brooks & Zakhari, 2013) cancers, suggesting that it can lead to dysregulated growth of cells and tissues. Finally, heavy alcohol consumption during pregnancy is the leading nongenetic cause of neurobehavioral impairment and a cluster of brain, craniofacial, cardiovascular, and skeletal developmental defects and growth deficits that are collectively termed the “fetal alcohol spectrum disorder” or FASD (Riley, Infante, & Warren, 2011). The varied neural and other organ effects attributable to alcohol exposure have resulted in the perception of alcohol as a “dirty drug” with pleotropic effects on tissues and organs. The large number of genes and cellular pathways that show alcohol sensitivity, if anything, emphasizes the perception that there is not a single, or at least limited, set of unifying principles to describe alcohol’s actions. However, recent evidence that alcohol interferes with epigenetic mechanisms for the first time advances the possibility of identifying a common mechanism for alcohol’s addictive effects, toxicity, and teratology. Epigenetic mechanisms may be most broadly defined as cellular processes that control and modify the output of genes without directly inducing gene mutations. Epigenetic control mechanisms like the methylation of DNA or the acetylation and methylation of histones may directly modify transcription from the genome by condensing sections of the genome into heterochromatin or conversely, by unwinding other regions of the genome into nuclear euchromatin, permit access to transcription factors. However, epigenetic regulatory mechanisms may operate on the transcriptome itself to regulate the translation of networks of protein-coding genes. A body of emerging evidence shows that a class of nonprotein-coding small RNA molecules called microRNAs (miRNAs) can mediate

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epigenetic control over both transcription and translation. Within the nucleus, miRNAs have been shown to recruit and control the assembly of heterochromatin complexes. In the cytoplasm, miRNAs recruit a complex of proteins termed the RNA-induced silencing complex (RISC) to shut down protein translation and to destabilize target messenger RNAs (mRNAs), perhaps including those that encode chromatin-modifying enzymes. Moreover, recent evidence suggests that miRNAs can serve as endocrine and paracrine signaling molecules. In their capacity to be secreted and act on target cells and tissues, miRNAs represent a novel class of intercellular epigenetic regulatory molecules. In this chapter, we assess emerging evidence for the role of miRNAs in mediating alcohol effects. As we will see, miRNAs have been implicated in alcohol addiction, toxicity, and teratology. These ethanol-sensitive miRNAs serve as loci for the control of networks of protein-coding genes, many of which regulate chromatin structure. Moreover, many ethanolsensitive miRNAs are transcribed from gene loci that are themselves under epigenetic control. These data collectively suggest that the analysis of miRNA biogenesis and function will yield useful clues about mechanisms underlying alcohol effects. Moreover, implicating miRNAs as mediators of alcohol effect offers the possibility that alcohol is not in fact a “dirty drug” but rather an agent that usurps control over epigenetic pathways to affect cellular and tissue adaptation.

2. miRNAs AND THEIR BIOGENESIS miRNAs belong to a broad class of nonprotein-coding RNA (ncRNA) molecules that are encoded within genomes of all plants and animals. With very few exceptions,1 ncRNAs were, until recently, generally viewed as transcriptional debris. The human genome sequencing efforts of the 1990s and early 2000s (chromosome 22 was the first to be mapped (Dunham et al., 1999), while the map of the largest chromosome, chromosome 1 was finally reported in 2006 (Gregory et al., 2006)) were predicted to result in a full and complete accounting of the complexity of human proteincoding genes, but additionally resulted in a reassessment of the status of ncRNAs in general. Annotation efforts showed that the human genome encoded scarcely 20,687 protein-coding genes compared to nearly a half-million or so 1

Ribosomal RNAs for example.

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enhancer and promoter sites (Dunham et al., 2012). Clearly, the human genome encodes much more than protein-coding mRNAs. It is ncRNAs, not protein-coding mRNAs, that constitute the dominant transcriptional output from the human genome. The absolute numbers of ncRNAs suggest that these molecules, rather than proteins, constitute the major locus of biological control within cells and tissues. The authoritative database for miRNAs, miRBase,2 documents 2578 mature miRNAs encoded in the human genome. This contingent of ncRNAs represents 1/10th the number of annotated protein-coding genes, but as we will see below, exerts major functional control over the output of proteincoding genes. miRNAs, as their name implies, are short ncRNA molecules, their final processed form, on average being 22 nucleotides (nt) in length. Not until 1993 did the first evidence emerge showing that miRNAs were indeed functional. A now seminal pair of papers (Lee, Feinbaum, & Ambros, 1993; Wightman, Ha, & Ruvkun, 1993) published in the same issue of the journal Cell identified a nematode-specific miRNA, lin-4, as a negative regulator of protein translation within cells. These papers together showed that lin-4 did not code for a protein, but rather, as small RNA molecule, expressed in two isoforms of 22 and 61 nt in length.3 Importantly, both papers showed that lin-4 was a negative regulator of translation of the developmentally important transcription factor, lin-14. These papers identified the 30 untranslated region (30 UTR) of lin-14 mRNA as a specific target for lin-4, and showed for the first time, that a small RNA molecule could regulate translation from an mRNA. While lin-4 is not evolutionarily conserved, subsequent investigations showed that translation inhibition by RNA interference (RNAi) was a common mechanism in all cells (Fire et al., 1998). Moreover, the second miRNA to be discovered, Let-7 (Reinhart et al., 2000), was found to be evolutionarily conserved (Pasquinelli et al., 2000). The combination of evidence for cellular RNAi mechanisms and Let-7 conservation lent strong support to the idea that miRNAs were indeed part of an endogenous and ubiquitous RNAi pathway (Hutvagner & Zamore, 2002), and a novel regulatory layer inserted between the transcriptome and proteome.

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Source: mirbase.org, human genome assembly GRCh37.p5. We now know that the 22 nt isoform represents the mature lin-4 miRNA and the 61 nt isoform represents a penultimate processing stage, termed a pre (premature)-miRNA.

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2.1. Biogenesis of miRNAs miRNAs are encoded within genomes, either as part of a long intergenic ncRNA (lincRNA) transcript (Fig. 7.1),4 or within intronic regions of protein-coding parent gene locus.5 Some miRNAs, like members of the miR-17-92 cluster, including miR-17a, miR-18a, miR-19a, miR-19-b1, miR-20a, and miR-92a-1 are clustered within a single lincRNA-encoding gene locus, MIR17HG (miR-17-92 cluster host gene). The initial gene products in the miRNA biogenic pathway, termed primary miRNA transcripts (pri-miRNAs), are transcribed by RNA polymerases II and III (Borchert, Lanier, & Davidson, 2006; Lee et al., 2004; Fig. 7.1). Many vertebrate miRNAs are transcribed within such primiRNA/lincRNA precursors which are estimated to between 1 and 10 kb in length (Saini, Enright, & Griffiths-Jones, 2008). For example, MIR17HG is estimated to be 5 kb in length.6 However, some pri-miRNAs can be much longer, ranging up to 33 kb for the miR-9-3 pri-miRNA precursor, to 434 kb for pri-miR-551b (Saini et al., 2008). Moreover, like mRNAs, pri-miRNA transcripts exhibit 50 -caps and 30 -poly adenylation (Cai, Hagedorn, & Cullen, 2004) and like mRNAs may undergo alternate splicing to generate transcript diversity (Mattioli, Pianigiani, & Pagani, 2013). Because of their length, conservation, and similarities to mRNAs, the possibility that pri-miRNAs may encode functions beyond miRNA biosynthesis cannot be ignored. For example, 50 -capping is required for nuclear export (Cheng et al., 2006) of RNA transcripts and may contribute to the observed localization of pri-miRNAs in extranuclear compartments like the postsynaptic densities of neurons (Lugli, Larson, Demars, & Smalheiser, 2012). The role of extranuclear pri-miRNAs remains to be ascertained, but these transcripts may provide a mechanism for synaptic activity-dependent local miRNA biogenesis and perhaps many other hitherto unsuspected functions. Another class of miRNAs are encoded within introns of protein-coding genes. For example, the ethanol-sensitive miRNAs, miR-153 and miR-335, are encoded within introns of the PTPRn-2 and MEST/Peg-1 protein-coding genes. Pre-mRNAs (containing both introns and exons) from such protein-coding loci may be directly directed to the miRNA biogenesis pathway, without prior 4

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miR-9-2, for example, is encoded within linc00461. Source: GRCh37/hg19 human genome assembly. miR-153-1 is encoded within the intron of the human PTPRN1 gene locus encoding a receptor tyrosine phosphatase. Locus NR_027350, source: http://www.ncbi.nlm.nih.gov/nuccore/NR_027350?report¼GenBank.

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Figure 7.1 Dominant model for miRNA biogenesis and function. Schematic depicts the specific instance of transcription of a miRNA-encoding ncRNA gene that may include both intron- and exon-coding regions. RNA polymerase II/III (Pol II/III)-dependent transcription from this type of locus results in the generation of a long ncRNA that is also termed the primary miRNA transcript (pri-miRNA) that is 50 -capped and 30 polyadenylated. This pri-miRNA transcript is subject to nuclear processing to generate a shorter, hairpin structure containing RNA termed the premature-miRNA (pre-miRNA) transcript. Pre-miRNAs are exported to the cytoplasm where they are additionally processed to generate a mature miRNA (the guide strand) and a passenger strand miRNA (miRNA*) that is often degraded. The mature miRNA is incorporated into an Argonaute (Ago-1–4)-containing RNA-induced silencing complex (RISC), which will target selected mRNA transcripts for translational repression or degradation. Other nontargeted mRNA transcripts may continue to retain translation activity.

spliceosome-mediated release of introns (Kim & Kim, 2007), suggesting that miRNA-encoding pre-mRNA transcripts, like their lincRNA counterparts, are in fact pri-miRNAs. Pri-miRNA transcripts are processed within the nucleus by the Drosha/ DGCR8 complex (Fig. 7.1; Han et al., 2004, 2006; Lee et al., 2003) into shorter 70 nt hairpin-like structures termed premature miRNAs (premiRNAs). Pre-miRNAs are transported from the nucleus to the cytoplasm by exportin-5 (Bohnsack, Czaplinski, & Gorlich, 2004; Lund, Guttinger,

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Calado, Dahlberg, & Kutay, 2004; Yi, Qin, Macara, & Cullen, 2003), where they are further cleaved by the type III RNAse, Dicer (Dicer-1; Bernstein, Caudy, Hammond, & Hannon, 2001; Zhang, Kolb, Brondani, Billy, & Filipowicz, 2002), releasing a short double-stranded RNA containing partly complementary 5-prime (5p) and 3-prime (3p) RNA fragments 22 nt in length. Generally, Dicer along with TRBP (trans-activation response (TAR) RNA-binding protein, TRBP2) preferentially loads one of these fragments, termed the guide strand, onto the chaperone protein Argonaute-2 (Ago-2; MacRae, Ma, Zhou, Robinson, & Doudna, 2008), while the other strand (termed the passenger strand or miRNA*) is preferentially degraded. Ago-2 along with its bound miRNA serves as the minimal RISC (MacRae et al., 2008). Peri-pubertal alcohol exposure in rodent models has recently been shown to result in dynamic temporal changes in both Drosha and Dicer mRNA transcripts (Prins, Przybycien-Szymanska, Rao, & Pak, 2014), and alcohol exposure in neural stem cell (NSC) cultures has been shown to result in accumulation of pre-miR-9-3 transcripts (Pappalardo-Carter et al., 2013), suggesting that miRNA processing may be broadly influenced by alcohol exposure. On the other hand, miRNA expression analyses (Balaraman et al., 2014; Guo, Chen, Carreon, & Qiang, 2012; Lewohl et al., 2011; Sathyan, Golden, & Miranda, 2007; Steenwyk, Janeczek, & Lewohl, 2013; Wang, Zhang, et al., 2009) indicate that alcohol exposure does not result in broad changes in miRNA expression, suggesting that miRNA processing may not be a significant target. Ago-2 is the member of the Argonaute family that is best associated with RISC function. While Argonaute family members Ago-1, Ago-2, Ago-3, and Ago-4 all have the capacity to bind miRNAs (Meister et al., 2004), only Ago-2 is known to exhibit “slicer” activity, i.e., the ability to engage in endonuclease activity resulting in degradation of target RNAs (Liu et al., 2004; Meister et al., 2004). If miRNAs were nondiscriminately loaded onto Ago proteins, it would suggest that with the exception of slicer activity, the RISCs associated with each Argonaute protein are functionally equivalent. However, recent data point to the existence of alternate processing of premiRNAs that bypass Dicer cleavage, and are instead, specifically processed by Ago-2 (Cheloufi, Dos Santos, Chong, & Hannon, 2010; Dueck, Ziegler, Eichner, Berezikov, & Meister, 2012). In their 2010 paper, Cheloufi and colleagues showed (Cheloufi et al., 2010) that some miRNAs like miR451 bypass Dicer processing in mammalian cells. Instead, pre-miR-451 appears to be directly processed by Ago-2, and, as Dueck and colleagues

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subsequently showed (Dueck et al., 2012), mature miR-451 preferentially localized to Ago-2. These data suggest that at least a subset of miRNAs show specific Argonaute protein preference and, consequently, support specific RISC functions associated with these proteins. While the mechanisms, which result in preferential selection of guide strand and elimination of passenger strand, are poorly understood, new research suggests that complex thermodynamic factors and composition of the RISC shape guide strand selection (Noland & Doudna, 2013). Interestingly, Ago-2 itself appears to exhibit intrinsic strand selectivity, and preference for guide strand loading, but that selectivity can be enhanced by the presence of alternate double-stranded RNA-binding proteins like PACT (Prkra, protein kinase, interferon-inducible double-stranded RNAdependent activator; Noland & Doudna, 2013).

3. MECHANISMS OF miRNA FUNCTION 3.1. Targeting 30 UTRs for mRNA degradation and translation repression The current dominant model for miRNA function is that miRNAs as a component of the RISC serve as negative regulators of mRNA stability and protein translation (Fig. 7.1) by binding to the 30 UTRs of target mRNAs (Grimson et al., 2007; Lewis, Burge, & Bartel, 2005). Individual miRNAs are known to target a network of several hundred protein-coding genes (Lim et al., 2005) to effect specific biological outcomes. Conversely, many miRNAs may target a common mRNA target, resulting in strong RISC control over mRNA stability and translation. 5p- and 3p-miRNAs are expected to have different target specificities, resulting in the regulation of different networks of protein-coding genes, though in the case of miR-9, for example, miR-9-5p and miR-9-3p have been found to regulate the mRNAs for REST (RE1-silencing transcription factor) and its cofactor, RCOR1/coREST (Packer, Xing, Harper, Jones, & Davidson, 2008) to coordinately regulate differentiation. Such selection is clearly an important component of RISC target specificity. Interestingly, ethanol exposure has been shown to regulate the expression of passenger strand miRNAs in a variety of model systems (Balaraman et al., 2014; Guo et al., 2012; Tal et al., 2012), implying alteration in the ratio of guide to passenger strand miRNAs. Such altered ratios may have significant consequences for downstream translation of gene networks.

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Reciprocally, many protein-coding genes, including genes important for neural development, like Doublecortin (DCX) and NeuroD1, have evolved extremely long 30 UTRs that may result in significant translation control by miRNAs. DCX, for example, which controls neuronal migration in the developing brain (Des Portes et al., 1998), is predicted to encode, in the human, a 30 UTR of 7.9 kb in size and is a predicted, evolutionarily conserved target for at least 10 different vertebrate miRNA families,7 and a potential target for at least an additional 17 mammalian-specific miRNA families.8 Importantly, an mRNA that encodes a single protein may nevertheless encode 30 UTRs that are variably sized, due to alternate splicing or alternate polyadenylation. Variably sized 30 UTRs will result in a proteincoding transcript with a range of susceptibility to miRNA-mediated translation regulation that may be cell and tissue specific (Majoros & Ohler, 2007). The human genome is currently annotated to encode 2578 miRNAs9 Estimates of effect suggest that each miRNA family on average targets more than 500 sites in 30 UTRs (Friedman et al., 2009). Moreover, of the estimated 20,687 protein-coding genes (Dunham et al., 2012), nearly 60% (Friedman et al., 2009) are estimated to be under 30 UTR-mediated miRNA control. Therefore, mRNA destabilization and translational repression are an important function of miRNAs. However, as we will see, this model of 30 UTR regulation of translation underestimates the biological complexity of miRNAs.

3.2. Alternate functions of miRNAs In the preceding section, we focused on evidence showing that miRNA activities at 30 UTR of target mRNAs result in translation inhibition and mRNA degradation. However, miRNA-binding sites have been identified in both 30 UTRs and 50 UTRs of the same target genes (Lee et al., 2009). Such alternate interactions with target mRNAs may result in variable and unpredictable outcomes. For example, a 2008 report showed that the miRNA miR-10a could bind to the 50 UTRs of mRNAs encoding ribosomal proteins to actually enhance translation (Orom, Nielsen, & Lund, 2008). Presumably, the translation of at least some target mRNAs may be 7

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Source: targetscan.org, based on analysis of NM_000555.3 locus (http://www.ncbi.nlm.nih.gov/ nuccore/NM_000555.3), including miRNA families with an aggregate probability of conservation (PCT) > 0.5 (Friedman, Farh, Burge, & Bartel, 2009). Analysis of the NM_000555.3 locus, based on the targetscan.org, total context score of 8 kb in length. The MECP2 30 UTR is a predicted and evolutionary conserved target for a large number of miRNAs (source: targetscan.org), and it is likely that these miRNAs collectively exert significant posttranscriptional control over MECP2 expression, and indirectly, chromatin remodeling.

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Figure 7.6 Sample model for miRNA–epigenetic pathway feedback loops, and potential model for epigenetic regulation by ethanol. (A) In this model, miRNAs may serve as translational repressors of DNA methylation enzymes and associated proteins. Repression of DNA methylation may in turn derepress miRNA expression. (B) In this model, ethanol may inhibit the expression of some miRNAs resulting in derepression of epigenetic machinery and further silencing of miRNA expression.

“crossveinless,” was transmitted over 23 generations, without any further exposure of any succeeding generation to a temperature shock. This transmission of an acquired trait over multiple generations was ultimately identified as an epigenetic mechanism, i.e., it was not due to gene mutations, but to some transmissible process that exerted control over gene expression. The “crossveinless” phenotype could be termed an “epimutation” that represented an ancestral adaptation to an environmental stimulus that was propagated to successive generations. Fetal alcohol exposure has been shown to result in persistent epimutations, i.e., persistent hypermethylation of the proopiomelanocortin (POMC) gene that is transmitted through the third generation via the male germline (Govorko, Bekdash, Zhang, & Sarkar, 2012). A role for miRNAs in transgenerational persistence of alcohol use disorders or FASD has not been established. However, recent and exciting evidence shows that early embryonic misexpression of an miRNA can result in heritable epimutations that persistent for several generations. An intriguing report (Grandjean et al., 2009) focused on the epimutation potential of miR-124, a miRNA that, like miR-9, is normally a critical determinant of brain development and neuronal differentiation (Conaco, Otto, Han, & Mandel, 2006; Krichevsky et al., 2006; Visvanathan, Lee, Lee, Lee, & Lee, 2007). In that report, Grandjean and colleagues microinjected miR-124 into fertilized eggs. They observed that this resulted in increased size of the embryo and that adult animals born following miR-124 microinjection, i.e., the F0 generation, were also found increased in size. Importantly, this phenotype of increased size was retained in the F1 generation and until the F2 generation. The authors showed that this effect was not due to

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increased expression of miR-124 per se. Rather, miR-124 was found to be homologous to a region within the promoter for the transcription factor Sox9. Microinjection of miR-124 into the F0 fertilized oocyte resulted in a transgenerational hypermethylation (and consequent inactivation) of the Sox9 promoter. The source of the epimutation due to miR-124 microinjection was, therefore, a persistent remodeling of the chromatin in a growth control gene locus. Interestingly, overexpression of miR-124 in spermatozoa resulted in a similar growth enhancement effect. It is possible that somatic tissue-enriched miRNAs like the brain-enriched miR-124 may be secreted and represent a somatic to germ cell transfer of information for epigenetic programming (Fig. 7.7). It is equally possible, even likely, that ethanol-mediated misexpression of miRNAs in the developing and adult organism will result in a range of epimutations that persist over multiple generations. As we have seen earlier, ethanol exposure during development and in the adult results in significant changes in miRNA profiles in tissues like the brain. The question is how do somatic changes in miRNA expression in organs like the brain result in germline transmission of epimutations. One possibility is that circulating miRNAs are a potential source of somatic to germline transmission of information (Sharma, 2014). This is an important possibility, since, as we have discussed earlier, ethanol exposure results in persistent changes in circulating (plasma) miRNA profiles in the adult and during development (Balaraman et al., 2014). It will be important to determine if one or more of these miRNAs are transferred to gametes, resulting in epigenetic reprogramming.

6. CONCLUSIONS In this chapter, we have discussed the involvement of a novel class of ncRNAs, miRNAs, in ethanol effects on the developing and adult organism. While miRNAs have an important function as negative regulators of protein translation, they also serve in a variety of roles. miRNAs localize to the nucleus where they control chromatin structure and consequently participate directly in the epigenetic programming of gene expression. They are also secreted and therefore should be considered to be signaling molecules and endocrine factors. The effects of secreted miRNAs on target tissues and cells could well include epigenetic reprogramming and the potential somatic to germ cell transmission of secreted miRNAs could be an important factor in the rise of epimutations and the transgenerational emergence of

Figure 7.7 Model for transgenerational transmission of somatic epimutations: somatic to germline transmission of miRNAs. miRNAs that are secreted by a variety of organs may be incorporated within germ cells and exert epigenetic control over early embryo development. An altered complement of circulating miRNAs released in response to disease or to environment alterations (e.g., drug exposure) may result in altered epigenetic programming information carried by the germ cells. Ago, Argonaute; RISC, RNA-induced silencing complex.

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disease. Ethanol clearly influences the expression of a large number of intracellular and extracellular miRNAs, and an understanding of miRNA biology will facilitate our understanding of the complex tissue adaptations that accompany alcohol consumption and the development of alcohol use disorders. Finally, as we discussed, miRNAs, particularly circulating miRNAs can be biomarkers for alcohol exposure in the adult and during development (Balaraman et al., 2014), and perhaps even predictors of alcohol effect and disease outcome. However, miRNAs can also be exploited as a novel class of drugs and therapeutic agents. For example, Selvamani and colleagues recently showed in an animal model that an antagonist to the miRNA Let-7f could protect against stroke, even if administered 4 h after the stroke (Selvamani, Sathyan, Miranda, & Sohrabji, 2012). The ability to reverse the course of a disease with a miRNA antagonist is an important finding that speaks to the potential for miRNA therapies to reverse the course of a broad range of diseases including perhaps alcoholism and alcohol-related birth defects. miRNA therapies may be engineered to either directly or indirectly manipulate the epigenetic landscape of cells and tissues to perhaps reverse addiction and even teratology.

ACKNOWLEDGMENTS Preparation of this chapter was supported in part by a grant from the NIAAA, R01AA013440, and by intramural support from the Women’s Health in Neuroscience Program at Texas A&M. We thank Elizabeth Thom for a critical review of the manuscript.

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