The Intertwining of Transposable Elements and Non-Coding RNAs

Growing evidence shows a close association of transposable elements (TE) with non-coding RNAs (ncRNA), and a significant number of small ncRNAs originate from TEs. Further, ncRNAs linked with TE sequences participate in a wide-range of regulatory functions. Alu elements in particular are critical players in gene regulation and molecular pathways. Alu sequences embedded in both long non-coding RNAs (lncRNA) and mRNAs form the basis of targeted mRNA decay via short imperfect base-pairing. Imperfect pairing is prominent in most ncRNA/target RNA interactions and found throughout all biological kingdoms. The piRNA-Piwi complex is multifunctional, but plays a major role in protection against invasion by transposons. This is an RNA-based genetic immune system similar to the one found in prokaryotes, the CRISPR system. Thousands of long intergenic non-coding RNAs (lincRNAs) are associated with endogenous retrovirus LTR transposable elements in human cells. These TEs can provide regulatory signals for lincRNA genes. A surprisingly large number of long circular ncRNAs have been discovered in human fibroblasts. These serve as “sponges” for miRNAs. Alu sequences, encoded in introns that flank exons are proposed to participate in RNA circularization via Alu/Alu base-pairing. Diseases are increasingly found to have a TE/ncRNA etiology. A single point mutation in a SINE/Alu sequence in a human long non-coding RNA leads to brainstem atrophy and death. On the other hand, genomic clusters of repeat sequences as well as lncRNAs function in epigenetic regulation. Some clusters are unstable, which can lead to formation of diseases such as facioscapulohumeral muscular dystrophy. The future may hold more surprises regarding diseases associated with ncRNAs andTEs.     

Transposable Elements and Stress in Vertebrates: An Overview

Since their identification as genomic regulatory elements, Transposable Elements (TEs) were considered, at first, molecular parasites and later as an important source of genetic diversity and regulatory innovations. In vertebrates in particular, TEs have been recognized as playing an important role in major evolutionary transitions and biodiversity. Moreover, in the last decade, a significant number of papers has been published highlighting a correlation between TE activity and exposition to environmental stresses and dietary factors. In this review we present an overview of the impact of TEs in vertebrate genomes, report the silencing mechanisms adopted by host genomes to regulate TE activity, and finally we explore the effects of environmental and dietary factor exposures on TE activity in mammals, which is the most studied group among vertebrates. The studies here reported evidence that several factors can induce changes in the epigenetic status of TEs and silencing mechanisms leading to their activation with consequent effects on the host genome. The study of TE can represent a future challenge for research for developing effective markers able to detect precocious epigenetic changes and prevent human diseases.     

Transposable Elements and Human Diseases: Mechanisms and Implication in the Response to Environmental Pollutants

Transposable elements (TEs) are recognized as major players in genome plasticity and evolution. The high abundance of TEs in the human genome, especially the Alu and Long Interspersed Nuclear Element-1 (LINE-1) repeats, makes them responsible for the molecular origin of several diseases. This involves several molecular mechanisms that are presented in this review: insertional mutation, DNA recombination and chromosomal rearrangements, modification of gene expression, as well as alteration of epigenetic regulations. This literature review also presents some of the more recent and/or more classical examples of human diseases in which TEs are involved. Whether through insertion of LINE-1 or Alu elements that cause chromosomal rearrangements, or through epigenetic modifications, TEs are widely implicated in the origin of human cancers. Many other human diseases can have a molecular origin in TE-mediated chromosomal recombination or alteration of gene structure and/or expression. These diseases are very diverse and include hemoglobinopathies, metabolic and neurological diseases, and common diseases. Moreover, TEs can also have an impact on aging. Finally, the exposure of individuals to stresses and environmental contaminants seems to have a non-negligible impact on the epigenetic derepression and mobility of TEs, which can lead to the development of diseases. Thus, improving our knowledge of TEs may lead to new potential diagnostic markers of diseases.     

Arabidopsis Toxicos en Levadura 12 Modulates Salt Stress and ABA Responses in Arabidopsis thaliana

Salt is one of the most common abiotic stresses, causing ionic and osmotic pressure changes that affect plant growth and development. In this work, we present molecular and genetic evidence that Arabidopsis Toxicos en Levadura 12 (ATL12) is involved in both salt stress and in the abscisic acid response to this stress. We demonstrate that ATL12 is highly induced in response to salt stress and that atl12 mutants have a lower germination rate, decreased root length, and lower survival rate compared to the Col-0 wild-type in response to salt stress. Overexpression of ATL12 increases expression of the salt stress-associated genes SOS1/2, and ABA-responsive gene RD29B. Additionally, higher levels of reactive oxygen species are detected when ATL12 is overexpressed, and qRT-PCR showed that ATL12 is involved in the AtRBOHD/F-mediated signaling. ATL12 expression is also highly induced by ABA treatment. Mutants of atl12 are hypersensitive to ABA and have a shorter root length. A decrease in water loss and reduced stomatal aperture were also observed in atl12 mutants in response to ABA. ABA-responsive genes RD29B and RAB18 were downregulated in atl12 mutants but were upregulated in the overexpression line of ATL12 in response to ABA. Taken together our results suggest that ATL12 modulates the response to salt stress and is involved in the ABA signaling pathway in Arabidopsis thaliana.     

Activation of Transposable Elements in Human Skeletal Muscle Fibers upon Statin Treatment

High cholesterol levels have been linked to a high risk of cardiovascular diseases, and preventative pharmacological care to lower cholesterol levels is critically important. Statins, which are hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, are drugs used to reduce the endogenous cholesterol synthesis, thus minimizing its pathophysiological effects. Despite the proven benefits, statins therapy is known to cause a number of skeletal muscle disorders, including myalgia, myopathy and myositis. The mechanisms underlying such statin-induced side effects are unknown. Recently, a group of genes and molecular pathways has been described to participate in statin-induced myopathy, caused by either simvastatin or rosuvastatin, although the mechanism by which changes in gene regulation occur was not studied. Transposable Elements (TEs), repetitive elements that move within the genome, are known to play regulatory roles in gene expression; however, their role in statin-induced muscle damage has not been studied. We analyzed the expression of TEs in human skeletal fiber cells treated with either simvastatin or rosuvastatin, as well as their respective controls, and identified TEs that change their expression in response to the treatment. We found that simvastatin resulted in >1000 differentially expressed (DE) TEs, whereas rosuvastatin resulted in only 27 DE TEs. Using network analysis tools, we predicted the impact of the DE TEs on the expression of genes and found that amongst the genes potentially modulated by TEs, there are some previously associated to statin-linked myopathy pathways (e.g., AKT3). Overall, our results indicate that TEs may be a key player in the statin-induced muscle side effects.     

DNA Methylation in Plant Responses and Adaption to Abiotic Stresses

Due to their sessile state, plants are inevitably affected by and respond to the external environment. So far, plants have developed multiple adaptation and regulation strategies to abiotic stresses. One such system is epigenetic regulation, among which DNA methylation is one of the earliest and most studied regulatory mechanisms, which can regulate genome functioning and induce plant resistance and adaption to abiotic stresses. In this review, we outline the most recent findings on plant DNA methylation responses to drought, high temperature, cold, salt, and heavy metal stresses. In addition, we discuss stress memory regulated by DNA methylation, both in a transient way and the long-term memory that could pass to next generations. To sum up, the present review furnishes an updated account of DNA methylation in plant responses and adaptations to abiotic stresses.     

Both Clathrin-Mediated and Membrane Microdomain-Associated Endocytosis Contribute to the Cellular Adaptation to Hyperosmotic Stress in Arabidopsis

As sessile organisms, plants must directly deal with an often complex and adverse environment in which hyperosmotic stress is one of the most serious abiotic factors, challenging cellular physiology and integrity. The plasma membrane (PM) is the hydrophobic barrier between the inside and outside environments of cells and is considered a central compartment in cellular adaptation to diverse stress conditions through dynamic PM remodeling. Endocytosis is a powerful method for rapid remodeling of the PM. In animal cells, different endocytic pathways are activated in response to osmotic stress, while only a few reports are related to the endocytosis response pathway and involve a mechanism in plant cells upon hyperosmotic stress. In this study, using different endocytosis inhibitors, the microdomain-specific dye di-4-ANEPPDHQ, variable-angle total internal reflection fluorescence microscopy (VA-TIRFM), and confocal microscopy, we discovered that internalized Clathrin Light Chain-Green Fluorescent Protein (CLC-GFP) increased under hyperosmotic conditions, accompanied by decreased fluorescence intensity of CLC-GFP at the PM. CLC-GFP tended to have higher diffusion coefficients and a fraction of CLC-GFP molecules underwent slower diffusion upon hyperosmotic stress. Meanwhile, an increased motion range of CLC-GFP was found under hyperosmotic treatment compared with the control. In addition, the order of the PM decreased, but the order of the endosome increased when cells were in hyperosmotic conditions. Hence, our results demonstrated that clathrin-mediated endocytosis and membrane microdomain-associated endocytosis both participate in the adaptation to hyperosmotic stress. These findings will help to further understand the role and the regulatory mechanism involved in plant endocytosis in helping plants adapt to osmotic stress.     

Epigenetic Regulation of the Hippocampus,with Special Reference to Radiation Exposure

The hippocampus is crucial in learning, memory and emotion processing, and is involved in the development of different neurological and neuropsychological disorders. Several epigenetic factors, including DNA methylation, histone modifications and non-coding RNAs, have been shown to regulate the development and function of the hippocampus, and the alteration of epigenetic regulation may play important roles in the development of neurocognitive and neurodegenerative diseases. This review summarizes the epigenetic modifications of various cell types and processes within the hippocampus and their resulting effects on cognition, memory and overall hippocampal function. In addition, the effects of exposure to radiation that may induce a myriad of epigenetic changes in the hippocampus are reviewed. By assessing and evaluating the current literature, we hope to prompt a more thorough understanding of the molecular mechanisms that underlie radiation-induced epigenetic changes, an area which can be further explored.     

Isoprene Emission Influences the Proteomic Profile of Arabidopsis Plants under Well-Watered and Drought-Stress Conditions

Isoprene is a small lipophilic molecule synthesized in plastids and abundantly released into the atmosphere. Isoprene-emitting plants are better protected against abiotic stresses, but the mechanism of action of isoprene is still under debate. In this study, we compared the physiological responses and proteomic profiles of Arabidopsis which express the isoprene synthase (ISPS) gene and emit isoprene with those of non-emitting plants under both drought-stress (DS) and well-watered (WW) conditions. We aimed to investigate whether isoprene-emitting plants displayed a different proteomic profile that is consistent with the metabolic changes already reported. Only ISPS DS plants were able to maintain the same photosynthesis and fresh weight of WW plants. LC–MS/MS-based proteomic analysis revealed changes in protein abundance that were dependent on the capacity for emitting isoprene in addition to those caused by the DS. The majority of the proteins changed in response to the interaction between DS and isoprene emission. These include proteins that are associated with the activation of secondary metabolisms leading to ABA, trehalose, and proline accumulations. Overall, our proteomic data suggest that isoprene exerts its protective mechanism at different levels: under drought stress, isoprene affects the abundance of chloroplast proteins, confirming a strong direct or indirect antioxidant action and also modulates signaling and hormone pathways, especially those controlling ABA synthesis. Unexpectedly, isoprene also alters membrane trafficking.     

Exploring the Contribution of Autophagy to the Excess-Sucrose Response in Arabidopsis thaliana

Autophagy is an essential intracellular eukaryotic recycling mechanism, functioning in, among others, carbon starvation. Surprisingly, although autophagy-deficient plants (atg mutants) are hypersensitive to carbon starvation, metabolic analysis revealed that they accumulate sugars under such conditions. In plants, sugars serve as both an energy source and as signaling molecules, affecting many developmental processes, including root and shoot formation. We thus set out to understand the interplay between autophagy and sucrose excess, comparing wild-type and atg mutant seedlings. The presented work showed that autophagy contributes to primary root elongation arrest under conditions of exogenous sucrose and glucose excess but not during fructose or mannitol treatment. Minor or no alterations in starch and primary metabolites were observed between atg mutants and wild-type plants, indicating that the sucrose response relates to its signaling and not its metabolic role. Extensive proteomic analysis of roots performed to further understand the mechanism found an accumulation of proteins essential for ROS reduction and auxin maintenance, which are necessary for root elongation, in atg plants under sucrose excess. The analysis also suggested mitochondrial and peroxisomal involvement in the autophagy-mediated sucrose response. This research increases our knowledge of the complex interplay between autophagy and sugar signaling in plants.     

Identification of Novel miRNAs and Their Target Genes in the Response to Abscisic Acid in Arabidopsis

miRNAs are involved in various biological processes, including adaptive responses to abiotic stress. To understand the role of miRNAs in the response to ABA, ABA-responsive miRNAs were identified by small RNA sequencing in wild-type Arabidopsis, as well as in abi1td, mkkk17, and mkkk18 mutants. We identified 10 novel miRNAs in WT after ABA treatment, while in abi1td, mkkk17, and mkkk18 mutants, three, seven, and nine known miRNAs, respectively, were differentially expressed after ABA treatment. One novel miRNA (miRn-8) was differentially expressed in the mkkk17 mutant. Potential target genes of the miRNA panel were identified using psRNATarget. Sequencing results were validated by quantitative RT-PCR of several known and novel miRNAs in all genotypes. Of the predicted targets of novel miRNAs, seven target genes of six novel miRNAs were further validated by 5′ RLM-RACE. Gene ontology analyses showed the potential target genes of ABA-responsive known and novel miRNAs to be involved in diverse cellular processes in plants, including development and stomatal movement. These outcomes suggest that a number of the identified miRNAs have crucial roles in plant responses to environmental stress, as well as in plant development, and might have common regulatory roles in the core ABA signaling pathway.     

Maternal Responses and Adaptive Changes to Environmental Stress via Chronic Nanomaterial Exposure: Differences in Inter and Transgenerational Interclonal Broods of Daphnia magna

There is increasing recognition that environmental nano-biological interactions in model species, and the resulting effects on progeny, are of paramount importance for nanomaterial (NM) risk assessment. In this work, Daphnia magna F0 mothers were exposed to a range of silver and titanium dioxide NMs. The key biological life history traits (survival, growth and reproduction) of the F1 intergenerations, at the first (F1B1), third (F1B3) and fifth (F1B5) broods, were investigated. Furthermore, the F1 germlines of each of the three broods were investigated over 3 more generations (up to 25 days each) in continuous or removed-from NM exposure, to identify how the length of maternal exposure affects the resulting clonal broods. Our results show how daphnids respond to NM-induced stress, and how the maternal effects show trade-offs between growth, reproduction and survivorship. The F1B1 (and following germline) had the shortest F0 maternal exposure times to the NMs, and thus were the most sensitive showing reduced size and reproductive output. The F1B3 generation had a sub-chronic maternal exposure, whereas the F1B5 generation suffered chronic maternal exposure where (in most cases) the most compensatory adaptive effects were displayed in response to the prolonged NM exposure, including enhanced neonate output and reduced gene expression. Transgenerational responses of multiple germlines showed a direct link with maternal exposure time to ‘sub-lethal’ effect concentrations of NMs (identified from standard OECDs acute toxicity tests which chronically presented as lethal) including increased survival and production of males in the F1B3 and G1B5 germlines. This information may help to fine-tune environmental risk assessments of NMs and prediction of their impacts on environmental ecology.