Summary Decapping represents a critical control point in regulating expression of protein coding genes. Here we demonstrate that decapping also modulates expression of long non-coding RNAs (lncRNAs). Specifically, levels of >100 lncRNAs in yeast are controlled by decapping and are degraded by a pathway that occurs independent of decapping regulators. We find many lncRNAs degraded by DCP2 are expressed proximal to inducible genes. Of these, we show several genes required for galactose utilization are associated with lncRNAs that have expression patterns inversely correlated with their mRNA counterpart. Moreover, decapping of these lncRNAs is critical for rapid and robust induction of GAL gene expression. Failure to destabilize a lncRNA known to exert repressive histone modifications results in perpetuation of a repressive chromatin state that contributes to reduced plasticity of gene activation. We propose that decapping and lncRNA degradation serve a vital role in transcriptional regulation specifically at inducible genes.

SUMMARY Adaptations that enable antimicrobial resistance often pose a fitness cost to the microorganism. Resistant pathogens must therefore overcome such fitness decreases to persist within their hosts. Here we demonstrate that the reduced fitness associated with one resistance-conferring mutation can be offset by community interactions with microorganisms harboring alternative mutations or via interactions with the human microbiota. Mutations that confer antibiotic resistance in the human pathogen Staphylococcus aureus led to decreased fitness whereas co-culture or co-infection of two distinct mutants resulted in collective recovery of fitness comparable to wildtype. Such fitness enhancements result from the exchange of metabolites between distinct mutants, leading to enhanced growth, virulence factor production, and pathogenicity. Inter-species fitness enhancements were also identified as members of the human microbiota can promote growth of antibiotic-resistant S. aureus. Thus, inter- and intra-species community interactions offset fitness costs and enable S. aureus to develop antibiotic resistance without loss of virulence.

Gram-positive bacteria cause the majority of skin and soft tissue infections (SSTIs), resulting in the most common reason for clinic visits in the United States. Recently, it was discovered that Gram-positive pathogens use a unique heme biosynthesis pathway, which implicates this pathway as a target for development of antibacterial therapies. We report here the identification of a small-molecule activator of coproporphyrinogen oxidase (CgoX) from Gram-positive bacteria, an enzyme essential for heme biosynthesis. Activation of CgoX induces accumulation of coproporphyrin III and leads to photosensitization of Gram-positive pathogens. In combination with light, CgoX activation reduces bacterial burden in murine models of SSTI. Thus, small-molecule activation of CgoX represents an effective strategy for the development of light-based antimicrobial therapies.

This work establishes a protein in the freshwater alga Chlamydomonas reinhardtii as an IsdG family heme oxygenase. This protein, LFO1, exhibits predicted secondary structure and catalytic residues conserved in IsdG family members, in addition to a chloroplast localization sequence. Additionally, the catabolite that results from the degradation of heme by LFO1 is distinct from that of other heme degradation products. Using LFO1 as a seed, we performed phylogenetic analysis, revealing that the IsdG family is conserved in all domains of life. Additionally, C. reinhardtii contains two previously identified HO-1 family heme oxygenases, making C. reinhardtii the first organism shown to contain two families of heme oxygenases. These data indicate that C. reinhardtii may have unique mechanisms for regulating iron homeostasis within the chloroplast.