Multi-level functional genomics reveals molecular and cellular oncogenicity of patient-based 3' untranslated region mutations.

3' untranslated region (3' UTR) somatic mutations represent a largely unexplored avenue of alternative oncogenic gene dysregulation. To determine the significance of 3' UTR mutations in disease, we identify 3' UTR somatic variants across 185 advanced prostate tumors, discovering 14,497 single-nucleotide mutations enriched in oncogenic pathways and 3' UTR regulatory elements. By developing two complementary massively parallel reporter assays, we measure how thousands of patient-based mutations affect mRNA translation and stability and identify hundreds of functional variants that allow us to define determinants of mutation significance.

Multiplexed functional genomic analysis of 5' untranslated region mutations across the spectrum of prostate cancer.

The functional consequences of genetic variants within 5' untranslated regions (UTRs) on a genome-wide scale are poorly understood in disease. Here we develop a high-throughput multi-layer functional genomics method called PLUMAGE (Pooled full-length UTR Multiplex Assay on Gene Expression) to quantify the molecular consequences of somatic 5' UTR mutations in human prostate cancer. We show that 5' UTR mutations can control transcript levels and mRNA translation rates through the creation of DNA binding elements or RNA-based cis-regulatory motifs.

A second riboswitch class for the enzyme cofactor NAD.

A bacterial noncoding RNA motif almost exclusively associated with genes was uncovered using comparative sequence analysis. Some PnuC proteins are known to transport nicotinamide riboside (NR), which is a component of the ubiquitous and abundant enzyme cofactor nicotinamide adenine dinucleotide (NAD). Thus, we speculated that the newly found " motif" RNAs might function as aptamers for a novel class of NAD-sensing riboswitches.

OapB forms a high-affinity complex with the P13 region of the noncoding RNA OLE.

Noncoding RNAs (ncRNAs) longer than 200 nucleotides are rare in bacteria, likely because bacterial genomes are under strong evolutionary pressures to maintain a small genome size. Of the long ncRNAs unique to bacteria, the OLE (ornate, large, extremophilic) RNA class is among the largest and most structurally complex. OLE RNAs form a ribonucleoprotein (RNP) complex by partnering with at least two proteins, OapA and OapB, that directly bind OLE RNA.

β-Caryophyllene protects against alcoholic steatohepatitis by attenuating inflammation and metabolic dysregulation in mice.

Background And Aims: β-Caryophyllene (BCP) is a plant-derived FDA approved food additive with anti-inflammatory properties. Some of its beneficial effects in vivo are reported to involve activation of cannabinoid CB receptors that are predominantly expressed in immune cells. Here, we evaluated the translational potential of BCP using a well-established model of chronic and binge alcohol-induced liver injury.