MicroRNA Functions in Stress Responses

Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Molecular cell (Impact Factor: 14.02). 10/2010; 40(2):205-15. DOI: 10.1016/j.molcel.2010.09.027
Source: PubMed


MicroRNAs (miRNAs) are a class of ∼22 nucleotide short noncoding RNAs that play key roles in fundamental cellular processes, including how cells respond to changes in environment or, broadly defined, stresses. Responding to stresses, cells either choose to restore or reprogram their gene expression patterns. This decision is partly mediated by miRNA functions, in particular by modulating the amount of miRNAs, the amount of mRNA targets, or the activity/mode of action of miRNA-protein complexes. In turn, these changes determine the specificity, timing, and concentration of gene products expressed upon stresses. Dysregulation of these processes contributes to chronic diseases, including cancers.

Download full-text


Available from: Anthony K. L. Leung, Sep 30, 2015
1 Follower
40 Reads
  • Source
    • "disease or oxidative stress status) can be stably inherited for a number of generations (Cuzin, Grandjean & Rassoulzadegan 2008). Indeed, miRNAs are suggested to play a large role in regulating the response to both acute and chronic environmental stress, by programming the cell's gene expression during development to be able to acclimatize to the new environment in the long run (Leung & Sharp 2010). Thus, their role in the processes of acclimatization and adaptation to urban habitats represents an intriguing venue for future research. "
    [Show abstract] [Hide abstract]
    ABSTRACT: 1.To estimate the impact of urbanisation on wild animals, it is important to know how different species, populations and/or individuals deal with and respond to environmental stress. Are more urbanised species adapted to their environment; or do individuals acclimatize over the course of their life? Alternatively, do they simply cope at the expense of other functions? These are three key processes that I will address using two important physiological responses as case traits, namely oxidative stress and inflammation, - which are known to be under genetic control as well as showing great plasticity.2.Oxidative stress is a state of more reactive oxidants than antioxidants, which may cause tissue damage linked to disease and senescence. Inflammation, on the other hand, is the response of vascular tissues to harmful stimuli. However, under progressive stimuli inflammation may also cause tissue destruction and pathology.3.Although patterns and strengths of effects are not always clear cut, the often interconnected oxidative stress and inflammation have the potential to be severely affected by urban stressors, thereby mechanistically link ecology to fitness. Here I discuss five major urban stressors: chemical-, noise- and artificial night light pollution, disease and diet, and how their individual and combinatory effects may affect these two physiological responses.4.To start to disentangle whether physiological responses are a question of evolving, acclimatizing or coping with the urban environment, population genetics along with regulatory mechanisms of gene expression will shed light on the “costs” of urban life, and help to understand why some species or genotypes thrive, while others are absent, in urban areas. Single gene polymorphism (SNP) has been successful for explaining local adaptation and tolerance towards acute toxic substances. However, for multiple stressors acting in concert, at low chronic exposure, investigations of epigenetic mechanisms regulating gene expression may be more illuminating.5.Here I review the pathways by which genetic and epigenetic mechanisms can affect oxidative stress and inflammatory responses in urban environments, thereby affecting overall fitness. By doing so, I identify the major outstanding gaps of knowledge in the interfaces between ecology, toxicology, evolutionary and molecular biology to inform future studies of urban wildlife.This article is protected by copyright. All rights reserved.
    Functional Ecology 05/2015; 29(7). DOI:10.1111/1365-2435.12477 · 4.83 Impact Factor
  • Source
    • "Emerging studies suggest that stress can alter miRNA biogenesis (Leung and Sharp, 2010). Our study revealed a direct and tight control of Drosha by stress conditions and an unexpected critical role of this regulation in cell survival. "
    [Show abstract] [Hide abstract]
    ABSTRACT: MicroRNAs (miRNAs) regulate the translational potential of their mRNA targets and control many cellular processes. The key step in canonical miRNA biogenesis is the cleavage of the primary transcripts by the nuclear RNase III enzyme Drosha. Emerging evidence suggests that the miRNA biogenic cascade is tightly controlled. However, little is known whether Drosha is regulated. Here, we show that Drosha is targeted by stress. Under stress, p38 MAPK directly phosphorylates Drosha at its N terminus. This reduces its interaction with DiGeorge syndrome critical region gene 8 and promotes its nuclear export and degradation by calpain. This regulatory mechanism mediates stress-induced inhibition of Drosha function. Reduction of Drosha sensitizes cells to stress and increases death. In contrast, increase in Drosha attenuates stress-induced death. These findings reveal a critical regulatory mechanism by which stress engages p38 MAPK pathway to destabilize Drosha and inhibit Drosha-mediated cellular survival. Copyright © 2015 Elsevier Inc. All rights reserved.
    Molecular Cell 02/2015; 57(4):721-734. DOI:10.1016/j.molcel.2015.01.004 · 14.02 Impact Factor
  • Source
    • "By evaluating concurrent changes in miRNA and mRNA levels, this work shines light on an additional layer of complexity to the gene expression changes occurring in the amygdala and ventral striatum. This is critical because miRNAs are thought to respond greatly to environmental stressors and are thought to mediate global gene expression changes [reviewed in Ref. (49, 50)]. "
    [Show abstract] [Hide abstract]
    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.
    Frontiers in Pediatrics 09/2014; 2:103. DOI:10.3389/fped.2014.00103
Show more