SUMMARY Genes expressing circadian RNA rhythms are enriched for metabolic pathways, however, the adaptive significance of cyclic gene expression remains unclear. We estimated the genome-wide synthetic and degradative cost of transcription and translation in three organisms and found that the cost of cycling genes is strikingly higher compared to non-cycling genes. Cycling genes are expressed at high levels and constitute the most costly proteins to synthesize in the genome. We demonstrate that metabolic cycling is accelerated in yeast grown under higher nutrient flux and the number of cycling genes increases ~40% - achieved by increasing the amplitude and not the mean level of gene expression. These results suggest that rhythmic gene expression optimizes the metabolic cost of global gene expression and that highly expressed genes have been selected to be down-regulated in a cyclic manner for energy conservation.

SUMMARY Forkhead box P2 (FOXP2) is a transcription factor expressed in the human brain that peaks during fetal development, and disruption in its ability to regulate downstream target genes leads to vulnerability to neurodevelopmental disorders. However, the mechanisms by which FOXP2 exerts regulatory control over targets during neuronal maturation have not been fully elucidated. Here, we use genome-wide chromatin accessibility assays and transcriptome-wide expression analyses in differentiating human neurons to show that FOXP2 represses proliferation-promoting genes in a DNA-binding-dependent manner. In contrast, FOXP2 and its cofactors, NFIA/B, activate neuronal maturation genes in a manner that does not require FOXP2 to interact with DNA directly. Moreover, comparisons with expression data from the developing human brain suggest that FOXP2/NFIA/B-dependent chromatin alterations drive maturation of excitatory cortical neurons. Thus, FOXP2 and its NFI cofactors may be specifically important for the development of cortical circuits underlying neurodevelopmental disorders.

Genetic studies have associated FOXP2 variation with speech and language disorders and other neurodevelopmental disorders (NDDs) involving pathology of the cortex. In this brain region, FoxP2 is expressed from development into adulthood, but little is known about its downstream molecular and behavioral functions. Here, we characterized cortex-specific Foxp2 conditional knockout mice and found a major deficit in reversal learning, a form of behavioral flexibility. In contrast, they showed normal activity levels, anxiety, and vocalizations, save for a slight decrease in neonatal call loudness. These behavioral phenotypes were accompanied by decreased cortical dopamine D1 receptor (D1R) expression at neonatal and adult stages, while general cortical development remained unaffected. Finally, using single-cell transcriptomics, we identified at least five excitatory and three inhibitory D1R-expressing cell types in neonatal frontal cortex, and we found changes in D1R cell type composition and gene expression upon cortical Foxp2 deletion. Strikingly, these alterations included non-cell-autonomous changes in upper layer neurons and interneurons. Together, these data support a role for Foxp2 in the development of dopamine-modulated cortical circuits and behaviors relevant to NDDs.

Pleiotropically acting eukaryotic corepressors such as retinoblastoma and SIN3 have been found to physically interact with many widely expressed “housekeeping” genes. Evidence suggests that their roles at these loci are not to provide binary on/off switches, as is observed at many highly cell‐type specific genes, but rather to serve as governors, directly modulating expression within certain bounds, while not shutting down gene expression. This sort of regulation is challenging to study, as the differential expression levels can be small. We hypothesize that depending on context, corepressors mediate “soft repression,” attenuating expression in a less dramatic but physiologically appropriate manner. Emerging data indicate that such regulation is a pervasive characteristic of most eukaryotic systems, and may reflect the mechanistic differences between repressor action at promoter and enhancer locations. Soft repression may represent an essential component of the cybernetic systems underlying metabolic adaptations, enabling modest but critical adjustments on a continual basis.

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FoxP2 encodes a forkhead box transcription factor required for the development of neural circuits underlying language, vocalization, and motor-skill learning. Human genetic studies have associated FOXP2 variation with neurodevelopmental disorders (NDDs), and within the cortex, it is coexpressed and interacts with other NDD-associated transcription factors. Cortical Foxp2 is required in mice for proper social interactions, but its role in other NDD-relevant behaviors and molecular pathways is unknown. Here, we characterized such behaviors and their potential underlying cellular and molecular mechanisms in cortex-specific Foxp2 conditional knockout mice. These mice showed deficits in reversal learning without increased anxiety or hyperactivity. In contrast, they emitted normal vocalizations save for a decrease in loudness of neonatal calls. These behavioral phenotypes were accompanied by decreases in cortical dopamine D1 receptor (D1R) expression at neonatal and adult stages, while general cortical development remained unaffected. Finally, using single-cell transcriptomics, we identified neonatal D1R-expressing cell types in frontal cortex and found changes in D1R cell type composition and gene expression upon cortical Foxp2 deletion. Together these data support a role for Foxp2 in the development of dopamine-modulated cortical circuits potentially relevant to NDDs.

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Staphylococcus aureus causes intramammary infections (IMIs), which are refractory to antibiotic treatment and frequently result in chronic mastitis. IMIs are the leading cause of conventional antibiotic use in dairy farms. Phage therapy represents an alternative to antibiotics to help better manage mastitis in cows, reducing the global spread of resistance. A mouse mastitis model of S. aureus IMI was used to study the efficacy of a new cocktail of five lytic S. aureus-specific phages (StaphLyse™), administered either via the intramammary (IMAM) route or intravenously (IV). The StaphLyse™ phage cocktail was stable in milk for up to one day at 37 °C and up to one week at 4 °C. The phage cocktail was bactericidal in vitro against S. aureus in a dose-dependent manner. A single IMAM injection of this cocktail given 8 h after infection reduced the bacterial load in the mammary glands of lactating mice infected with S. aureus, and as expected, a two-dose regimen was more effective. Prophylactic use (4 h pre-challenge) of the phage cocktail was also effective, reducing S. aureus levels by 4 log10 CFU per gram of mammary gland. These results suggest that phage therapy may be a viable alternative to traditional antibiotics for the control of S. aureus IMIs.