The Body-wide Transcriptome Landscape of Disease Models

Abstract

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.

Interleukin‐36α as a potential biomarker for renal tubular damage induced by dietary phosphate load

“…All animal experiments were approved by the Institutional Animal Care and Use Committee from Jichi Medical University (approval number 18003‐01). Male C57BL/6J mice at 8 weeks of age were subjected to either right UNx or sham operation (laparotomy alone) as previously described [5]. Four weeks after the surgery, the mice were placed on a diet containing 0.35%, 1.0%, 1.5%, or 2.0% inorganic phosphate for 10 days.…”

“…To obtain a clue to understand the mechanism, we previously performed RNA sequencing analysis using kidneys from uninephrectomized mice fed the high‐phosphate diet (2.0% inorganic phosphate) and from sham‐operated mice fed the regular diet (0.35% inorganic phosphate) [5]. Besides expression of markers for renal tubular damage including Osteopontin, neutrophil gelatinase‐associated lipocalin (Ngal), and kidney injury molecule‐1 (Kim‐1), expression of several inflammatory cytokines and chemokines was upregulated, suggesting that inflammation might play a critical role in the phosphate‐induced kidney damage.…”

Cell type-specific weighting-factors to solve solid organs-specific limitations of single cell RNA-sequencing

“…The results show that the Pearson correlation coefficients are less than 0.75 for 10 organs (aorta, brain, heart, large intestine, liver, lung, pancreas, skin, skeletal muscle, thymus) ( Figure 2A). Such large gaps are unlikely due to sex or strain differences, as both the whole-organ and single-cell RNA-seq are derived from the same sex (male) and strain, C57BL6, (Han et al, 2018;Kozawa et al, 2019;Kozawa et al, 2018;Tabula Muris et al, 2018), except for the skeletal muscle where its scRNA-seq data are derived from female mice. This result suggests the common assumption of the other methods that the whole-organ/bulk-tissue RNA-seq is the sum of the normalized transcript counts of each composite cell-type weighted by cell-type ratios must be reevaluated.…”

“…Due to the cell-dissociation/-purification steps, it is a difficult, and often an impractical, task to conduct scRNA-seq of multiple organs from the identical experimental model organism. This is often necessary in many experimental situations such as the study of the drug effects and/or pathogenesis on/in multiple organs in the same subject (Kozawa et al, 2018).…”

“…We evaluated mouse organs, instead of human organs, as many organs and paired single-cell RNA-seq datasets are readily available (Han et al, 2018;Kozawa et al, 2018;Tabula Muris et al, 2018).…”