Oakley, R. | bioRxiv Science

bioRxiv2026

Methionine Deprivation-induced Reprogramming of Hepatic Rhythms Is Mediated by Glucocorticoid Receptor

The circadian clock tightly interacts with cellular metabolism, and nutritional challenges can profoundly remodel its function. Dietary methionine restriction has been shown to improve metabolic health and extend lifespan. However, whether and how dietary methionine restriction impacts the circadian clock is unclear. Here, we demonstrate that methionine deprivation (MD) in the mouse induces alterations in multiple signaling systems, inducing rhythmic biological events in liver that are entrained by feeding time rather than day/light cycles. Alteration in growth factor signaling leads to loss of activation of a pioneer transcription factor, STAT5, which normally directs rhythmic chromatin localization of the glucocorticoid receptor (GR). Loss of active STAT5 leads to reprogramming of the epigenome and of the GR-directed transcriptome in a manner abolished by liver-specific deletion of GR. These results demonstrate that dietary methionine restriction remodels the circadian biological program directed by glucocorticoid receptor.

genomics↗

bioRxiv2022

Respiratory strategy at birth initiates distinct lung injury phenotypes in the preterm lamb lung

Bronchopulmonary disease is the chronic manifestation of the acute injury that may accompany ventilation following preterm birth. A lack of clear trial evidence often hampers clinical decision-making during support of the preterm lung at birth. Protein biomarkers have been used to define acute lung injury phenotypes and improve patient selection for specific interventions in adult respiratory distress syndrome. Here we present a mass spectrometry-based approach to profile the protein phenotype associated with three different aeration strategies known to cause different pathophysiological responses when applied at birth to preterm lambs. We were able to identify pathway enrichments specific to both ventilation strategy and lung regions based upon gravity-dependency. Ventilation strategy-specific phenotypes were further delineated by applying partial least square modelling to identify associations between specific proteins and clinical, physiological and morphological outcomes. This work highlights the specificity of lung injury responses to routinely applied birth interventions such as different respiratory support approaches and identified the molecular events associated with each. Furthermore, we demonstrate the capacity to subdivide preterm infants by the direct aetiology and response to lung injury; the first step towards true precision medicine in neonatology.

systems biology↗