SummaryVirtually all diseases affect multiple organs. However, our knowledge of the body-wide effects remains limited. Here, we report the body-wide transcriptome landscape across 13–23 organs of mouse models of myocardial infarction, diabetes, kidney diseases, cancer, and pre-mature aging. Using such datasets, we find (1) differential gene expression in diverse organs across all models; (2) skin as a disease-sensor organ represented by disease-specific activities of putative gene-expression network; (3) a bone-skin cross talk mediated by a bone-derived hormone, FGF23, in response to dysregulated phosphate homeostasis, a known risk-factor for kidney diseases; (4) candidates for the signature activities of many more putative inter-organ cross talk for diseases; and (5) a cross-species map illustrating organ-to-organ and model-to-disease relationships between human and mouse. These findings demonstrate the usefulness and the potential of such body-wide datasets encompassing mouse models of diverse disease types as a resource in biological and medical sciences. Furthermore, the findings described herein could be exploited for designing disease diagnosis and treatment.

Approximately 90% of pre-clinically validated drugs fail in clinical trials owing to unanticipated clinical outcomes, costing over several hundred million US dollars per drug. Despite such critical importance, translating pre-clinical data to clinical outcomes remain a major challenge. Herein, we designed a modality-independent and unbiased approach to predict clinical outcomes of drugs. The approach exploits their multi-organ transcriptome patterns induced in mice and a unique mouse-transcriptome database ''humanized'' by machine learning algorithms and human clinical outcome datasets. The cross-validation with small-molecule, antibody, and peptide drugs shows effective and efficient identification of the previously known outcomes of 5,519 adverse events and 11,312 therapeutic indications. In addition, the approach is adaptable to deducing potential molecular mechanisms underlying these outcomes. Furthermore, the approach identifies previously unsuspected repositioning targets. These results, together with the fact that it requires no prior structural or mechanistic information of drugs, illustrate its versatile applications to drug development process.

The cardiovascular system facilitates body-wide distribution of oxygen, a vital process for the development and survival of virtually all vertebrates. However, the zebrafish, a vertebrate model organism, appears to form organs and survive mid-larval periods without a functional cardiovascular system. Despite such dispensability, it is the first organ to develop. Such enigma prompted us to hypothesize other cardiovascular functions that are important for developmental and/or physiological processes. Hence, systematic cellular ablations and functional perturbations were performed on the zebrafish cardiovascular system to gain comprehensive and body-wide understanding of such functions and to elucidate the underlying mechanisms. This approach identifies a set of organ-specific genes, each implicated for important functions. The study also unveils distinct cardiovascular mechanisms, each differentially regulating their expressions in organ-specific and oxygen-independent manners. Such mechanisms are mediated by organ-vessel interactions, circulation-dependent signals, and circulation-independent beating-heart-derived signals. A comprehensive and body-wide functional landscape of the cardiovascular system reported herein may provide clues as to why it is the first organ to develop. Furthermore, these data could serve as a resource for the study of organ development and function.

The cardiovascular system facilitates body-wide distribution of oxygen, a vital process for development and survival of virtually all vertebrates. However, zebrafish, a vertebrate model organism, appears to form organs and survive mid-larval periods without the functional cardiovascular system. Despite such dispensability, it is the first organ to develop. Such enigma prompted us to hypothesize yet other cardiovascular functions that are important for developmental and/or physiological processes. Hence, systematic cellular ablations and functional perturbations are performed on zebrafish cardiovascular system to gain comprehensive and body-wide understanding of such functions and to elucidate underlying mechanisms. This approach identifies a set of organ-specific genes, each implicated for important functions. The study also unveils distinct cardiovascular mechanisms, each differentially regulating their expressions in organ-specific and oxygen-independent manners. Such mechanisms are mediated by organ-vessel interactions, circulation-dependent signals, and circulation-independent beating-heart-derived signals. Hence, a comprehensive and body-wide functional landscape of the cardiovascular system reported herein may provide a clue as to why it is the first organ to develop. Furthermore, the dataset herein could serve as a resource for the study of organ development and function.SUMMARY STATEMENTThe body-wide landscape of the cardiovascular functions during development is reported. Such landscape may provide a clue as to why the cardiovascular system is the first organ to develop.