Dysregulation of microRNA Expression and Function Contributes to the Etiology of Fetal Alcohol Spectrum Disorders

Department of Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center, Bryan, Texas, USA.
Alcohol research : current reviews 03/2013; 35(1):18-24.
Source: PubMed


MicroRNAs (miRNAs) are members of a large class of non-protein-coding RNA (ncRNA) molecules that represent a significant, but until recently unappreciated, layer of cellular regulation. Assessment of the generation and function of miRNAs suggests that these ncRNAs are vulnerable to interference from genetic, epigenetic, and environmental factors. A small but rapidly expanding body of studies using a variety of animal- and cell culture-based experimental models also has shown that miRNAs are important targets of alcohol during fetal development and that their dysregulation likely plays a significant role in the etiology of fetal alcohol spectrum disorders (FASD). Accordingly, an analysis of the regulation and function of these miRNAs may yield important clues to the management of FASD.

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Available from: Rajesh C Miranda, Jan 27, 2015
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    • "In neurons, miRNAs also play a role in compartmentalizing specific mRNA translation in subcellular components, including axons (13) and synapses [reviewed in Ref. (14)]. Dysregulation of miRNAs have recently been associated with a variety of neurodegenerative diseases as well as alcohol consumption in human beings (15) and rodent fetal exposure models [reviewed in Ref. (16)]. "
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    ABSTRACT: Fetal alcohol spectrum disorders (FASDs) are associated with abnormal social behavior. These behavioral changes may resemble those seen in autism. Rats acutely exposed to ethanol on gestational day 12 show decreased social motivation at postnatal day 42. We previously showed that housing these ethanol-exposed rats with non-exposed controls normalized this deficit. The amygdala is critical for social behavior and regulates it, in part, through connections with the basal ganglia, particularly the ventral striatum. MicroRNAs (miRNAs) are short, hairpin-derived RNAs that repress mRNA expression. Many brain disorders, including FASD, show dysregulation of miRNAs. In this study, we tested if miRNA and mRNA networks are altered in the amygdala and ventral striatum as a consequence of prenatal ethanol exposure and show any evidence of reversal as a result of social enrichment. RNA samples from two different brain regions in 72 male and female adolescent rats were analyzed by RNA-Seq and microarray analysis. Several miRNAs showed significant changes due to prenatal ethanol exposure and/or social enrichment in one or both brain regions. The top predicted gene targets of these miRNAs were mapped and subjected to pathway enrichment analysis. Several miRNA changes caused by ethanol were reversed by social enrichment, including mir-204, mir-299a, miR-384-5p, miR-222-3p, miR-301b-3p, and mir-6239. Moreover, enriched gene networks incorporating the targets of these miRNAs also showed reversal. We also extended our previously published mRNA expression analysis by directly examining all annotated brain-related canonical pathways. The additional pathways that were most strongly affected at the mRNA level included p53, CREB, glutamate, and GABA signaling. Together, our data suggest a number of novel epigenetic mechanisms for social enrichment to reverse the effects of ethanol exposure through widespread influences on gene expression.
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    • "In addition, it is implicated in long-lasting alterations in DNA methylation in imprinted domains that harbor non-coding RNAs (Balaraman et al., 2013; Laufer et al., 2013). Together, these data support the " fetal origin of adult disease " hypothesis predicted by Barker (2004). "
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    ABSTRACT: Fetal alcohol spectrum disorder (FASD) presents a collection of symptoms representing physiological and behavioral phenotypes caused by maternal alcohol consumption. Symptom severity is modified by genetic differences in fetal susceptibility and resistance as well as maternal genetic factors such as maternal alcohol sensitivity. Animal models demonstrate that both maternal and paternal genetics contribute to the variation in the fetus' vulnerability to alcohol exposure. Maternal and paternal genetics define the variations in these phenotypes even without the effect of alcohol in utero, as most of these traits are polygenic, non-Mendelian, in their inheritance. In addition, the epigenetic alterations that instigate the alcohol induced neurodevelopmental deficits can interact with the polygenic inheritance of respective traits. Here, based on specific examples, we present the hypothesis that the principles of non-Mendelian inheritance, or "exceptions" to Mendelian genetics, can be the driving force behind the severity of the prenatal alcohol-exposed individual's symptomology. One such exception is when maternal alleles lead to an altered intrauterine hormonal environment and, therefore, produce variations in the long-term consequences on the development of the alcohol-exposed fetus. Another exception is when epigenetic regulation of allele-specific gene expression generates disequilibrium between the maternal vs. paternal genetic contributions, and thereby, modifies the effect of prenatal alcohol exposure on the fetus. We propose that these situations in which one parent has an exaggerated influence over the offspring's vulnerability to prenatal alcohol are major contributing mechanisms responsible for the variations in the symptomology of FASD in the exposed generation and beyond.
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    ABSTRACT: The etiology of many brain diseases remains allusive to date after intensive investigation of genomic background and symptomatology from the day of birth. Emerging evidences indicate that a third factor, epigenetics prior to the birth, can exert profound influence on the development and functioning of the brain and over many neurodevelopmental syndromes. This chapter reviews how aversive environmental exposure to parents might predispose or increase vulnerability of offspring to neurodevelopmental deficit through alteration of epigenetics. These epigenetic altering environmental factors will be discussed in the category of addictive agents, nutrition or diet, prescriptive medicine, environmental pollutant, and stress. Epigenetic alterations induced by these aversive environmental factors cover all aspects of epigenetics including DNA methylation, histone modification, noncoding RNA, and chromatin modification. Next, the mechanisms how these environmental inputs influence epigenetics will be discussed. Finally, how environmentally altered epigenetic marks affect neurodevelopment is exemplified by the alcohol-induced fetal alcohol syndrome. It is hoped that a thorough understanding of the nature of prenatal epigenetic inputs will enable researchers with a clear vision to better unravel neurodevelopmental deficit, late-onset neuropsychiatric diseases, or idiosyncratic mental disorders.
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