Search Results for: incrna
Ahmad M. Khalil, PhD, knew the odds were against him — as in thousands upon thousands to one.
Yet he and his team never wavered from their quest to identify the parts of the body responsible for revving up one of the most aggressive forms of breast cancer, HER2+. This month in Breast Cancer Research and Treatment, Khalil and his colleagues at Case Western Reserve University proved the power of persistence; from a pool of more than 30,000 possibilities, they found 38 genes and molecules that most likely trigger HER2+ cancer cells to spread.
By narrowing what was once an overwhelming range of potential culprits to a relatively manageable number, Khalil and his team dramatically increased the chances of identifying successful treatment approaches to this particularly pernicious form of breast cancer. The HER2+ subtype accounts for approximately 20 to 30 percent of early-stage breast cancer diagnoses, which are estimated to be more than 200,000 new breast cancer diagnoses each year in this country, leading to approximately 40,000 deaths annually. Several cancer chemotherapy drugs do work well at early stages of the disease — destroying 95 to 98 percent of the cancer cells in HER2+ tumors.
An explanation of what lincRNA is, how it was discovered, and a special emphasis on TUNA, a recently discovered lincRNA.
Tissue-Specific RNA-Seq in Human Evoked Inflammation Identifies Blood and Adipose LincRNA Signatures
Inappropriate transcriptional activation of innate immunity is a pathological feature of several cardiometabolic disorders, but little is known about inflammatory modulation of long intergenic noncoding RNAs (lincRNAs) in disease-relevant human tissues.
Researchers at the University of Pennsylvania applied deep RNA sequencing (>500 million filtered reads per sample) to blood and adipose during low-dose experimental endotoxemia (lipopolysaccharide) in a healthy human, with targeted replication in separate individuals undergoing endotoxemia (n=6), to identify inflammatory lincRNAs. A subset of these lincRNAs was examined for expression in adipocytes and monocytes, modulation in adipose of obese humans, and overlap with genome-wide association study signals for inflammatory and cardiometabolic traits. Of a stringent set of 4284 lincRNAs, ≈11% to 22% were expressed with 201 and 56 lincRNAs modulated by lipopolysaccharide in blood or adipose, respectively. Tissue-specific expression of a subset of 6 lipopolysaccharide-lincRNAs was replicated with lipopolysaccharide modulation confirmed for all 3 expressed in blood and 2 of 4 expressed in adipose. The broader generalizability of findings in blood of subject A was confirmed by RNA sequencing in 7 additional subjects. The researchers confirmed adipocytes and monocytes as potential cell-sources of selective lipopolysaccharide-regulated lincRNAs, and 2 of these, linc-DMRT2 (P=0.002) and linc-TP53I13 (P=0.01), were suppressed in adipose of obese humans. Finally, they provide examples of lipopolysaccharide-modulated lincRNAs that overlap single nucleotide polymorphisms that are associated with cardiometabolic traits.
These findings provide novel insights into tissue-level, inflammatory transcriptome regulation in cardiometabolic diseases. These are complementary to more usual approaches limited to interrogation of DNA variations.
- Liu Y1, Ferguson JF, Xue C, Ballantyne RL, Silverman IM, Gosai SJ, Serfecz J, Morley MP, Gregory BD, Li M, Reilly MP. (2014) Tissue-Specific RNA-Seq in Human Evoked Inflammation Identifies Blood and Adipose LincRNA Signatures of Cardiometabolic Diseases. Arterioscler Thromb Vasc Biol 34(4), 902-12. [abstract]
Many studies are uncovering functional roles for long noncoding RNAs (lncRNAs), yet few have been tested for in vivo relevance through genetic ablation in animal models. To investigate the functional relevance of lncRNAs in various physiological conditions, a team led by researchers at Harvard University have developed a collection of 18 lncRNA knockout strains in which the locus is maintained transcriptionally active. Initial characterization revealed peri- and postnatal lethal phenotypes in three mutant strains (Fendrr, Peril, and Mdgt), the latter two exhibiting incomplete penetrance and growth defects in survivors. The team also report growth defects for two additional mutant strains (linc-Brn1b and linc-Pint). Further analysis revealed defects in lung, gastrointestinal tract, and heart in Fendrr(-/-) neonates, whereas linc-Brn1b(-/-) mutants displayed distinct abnormalities in the generation of upper layer II-IV neurons in the neocortex. This study demonstrates that lncRNAs play critical roles in vivo and provides a framework and impetus for future larger-scale functional investigation into the roles of lncRNA molecules.
- Sauvageau M et al. (2013) Multiple knockout mouse models reveal lincRNAs are required for life and brain development. Elife 2(0), e01749. [article]