Alterations in metabolic pathways were recently recognized as potential underlying drivers of idiopathic pulmonary fibrosis (IPF), translating into novel therapeutic targets. However, knowledge of metabolic and lipid regulation in fibrotic lungs is limited. To comprehensively characterize metabolic perturbations in the Bleomycin mouse model of IPF we analyzed the metabolome and lipidome by mass spectrometry. We identified increased tissue turnover and repair, evident by enhanced breakdown of proteins, nucleic acids, lipids and ECM turnover. Energy production was upregulated, including glycolysis, tricarboxylic acid (TCA) cycle, glutaminolysis, lactate production and increased fatty acid oxidation. Higher eicosanoid synthesis indicated inflammatory processes. Since the risk of IPF increases with age, we investigated how age influences metabolomic and lipidomic changes in the Bleomycin-induced pulmonary fibrosis model. Surprisingly, except cytidine, we did not detect any significantly differential metabolites or lipids between old and young Bleomycin-treated lungs. Together, we identified metabolomic and lipidomic changes in fibrosis that reflect higher energy demand, proliferation, tissue remodeling, collagen deposition and inflammation that might serve for improving diagnostic and therapeutic options for fibrotic lung diseases in the future.

Mammalian specification of mesoderm and definitive endoderm (DE) is instructed by the two related Tbx transcription factors (TFs) Eomesodermin (Eomes) and Brachyury sharing partially redundant functions. Gross differences of mutant embryonic phenotypes suggest specific functions of each TF. To date, the molecular details of separated lineage-specific gene-regulation by Eomes and Brachyury remain poorly understood. Here, we combine embryonic and stem cell-based analyses to delineate the non-overlapping, lineage-specific transcriptional activities. On a genome-wide scale binding of both TFs overlaps at promoters of target genes, but shows specificity for distal enhancer regions, that is conferred by differences in Tbx DNA-binding motifs. The unique binding to enhancer sites instructs the specification of anterior mesoderm (AM) and DE by Eomes and caudal mesoderm by Brachyury. Remarkably, EOMES antagonizes BRACHYURY gene-regulatory functions in co- expressing cells during early gastrulation to ensure the proper sequence of early AM and DE lineage specification followed by posterior mesoderm derivatives.

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