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Archive - Dec 20, 2013

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Retrotransposon DNA Proliferates in Aging Tissues

The genomes of organisms from humans to corn are replete with "parasitic" strands of DNA that, when not suppressed, copy themselves and spread throughout the genome, potentially affecting health. Earlier this year, Brown University researchers found that these "retrotransposable elements" (RTEs) were increasingly able to break free of the genome's control in cultures of human cells. Now, the researchers have shown that RTEs are increasingly able to break free and copy themselves in the tissues of mice as the animals aged. In further experiments, the biologists showed that this activity was readily apparent in cancerous tumors, but that it also could be reduced by restricting calories. "As mice age, we are seeing deregulation of these elements and they begin to be expressed and increase in copy number in the genome," said Dr. Jill Kreiling, a research assistant professor at Brown, and leader of the study published online on December 7, 2013 in an open-access article in the journal Aging. "This may be a very important mechanism in leading to genome instability. A lot of the chronic diseases associated with aging, such as cancer, have been associated with genome instability." Whether the proliferation of RTEs is exclusively a bad thing remains a hot question among scientists, but what they do know is that the genome tries to control RTEs by wrapping them up in a tightly wound configuration called heterochromatin. In their experiments, Dr. Kreiling and co-corresponding author Professor John Sedivy found that overall, the genomes of several mouse tissues become more heterochromatic with age. But they also found, paradoxically, that some regions where RTEs are concentrated became - loosened up instead , particularly after mice reached the 2-year mark (equivalent to about the 70-year mark for a person).

Multiple Enhancer Variant Hypothesis for Susceptibility to Common Disease

Many rare disorders, like sickle cell anemia, are caused by gene mutation. Yet, until now, the underlying genetic cause of more common conditions – for example, rheumatoid arthritis – has eluded scientists for years. New research from Case Western Reserve University School of Medicine finds that six common diseases arise from DNA changes located outside genes. The study from the laboratory of Peter Scacheri, Ph.D., shows that multiple DNA changes, or variants, work in concert to affect genes, leading to autoimmune diseases including rheumatoid arthritis. Further, for each disease, multiple different genes are manipulated by several small differences in DNA. The study is entitled, “Combinatorial Effects of Multiple Enhancer Variants in Linkage Disequilibrium Dictate Levels of Gene Expression to Confer Susceptibility to Common Traits.” In the study, the authors present evidence that for six common autoimmune disorders (rheumatoid arthritis, Crohn’s disease, celiac disease, multiple sclerosis, lupus, and ulcerative colitis) genome-wide associations arise from multiple polymorphisms in linkage disequilibrium that map to clusters of enhancer elements active in the same cell type. The authors say that this finding suggests a “multiple enhancer variant” hypothesis for common traits, whereby several variants in linkage disequilibrium impact multiple enhancers and cooperatively affect gene expression. They go on to show that multiple enhancer variants within a given locus typically target the same gene. The authors conclude that the “multiple enhancer variant” hypothesis offers a new paradigm by which non-coding variants can confer susceptibility to common traits. The research was published online on November 6, 2013 in Genome Research.

First Description of Mechanism for Selective Sorting of miRNAs into Exosomes

The role of microRNAs (miRNAs) is fundamental for the correct moment-to-moment adjustment in the expression of target genes. "Before this study, we already knew that these small molecules could be packaged into small vesicles (exosomes) and exported to the extracellular space, to be later captured by other cells and in this way play an important role in intercellular communication," explains CNIC (Centro Nacional de Investigaciones Cardiovascularis in Madrid, Spain) researcher Carolina Villarroya, the first author on a study published online on December 20, 2013 in an open-access article in Nature Communications. The study was entitled, “Sumoylated hnRNPA2B1 Controls the Sorting of miRNAs into Exosomes through Binding to Specific Motifs.” What was not known until now was the mechanism by which miRNAs are encapsulated and exported. And this is precisely what graduate researcher Villarroya and Dr. María Mittelbrunn—from Professor Sánchez Madrid's group—have discovered, working closely with Dr. Fátima Sánchez Cabo of the Bioinformatics Unit and Dr. Jesús Vázquez of the Proteomics Unit. The Nature Communications article describes how a specific group of miRNAs that are actively exported in nanovesicles (exosomes) from human T lymphocytes share specific nucleotide sequence patterns called EXOmotifs. When these EXOmotifs are mutated, export of these miRNAs is impeded; and when they are introduced into other miRNAs, export is facilitated. EXOmotifs provide the binding site for a protein called hnRNPA2B1, which is responsible for transporting miRNAs to the interior of exosomes. hnRNPA2B1 is also implicated in the transport of the genomic RNA of viruses such as HIV to sites of exit to the cell exterior.