Physiological and pathophysiological differences widely exist in paired organ systems. However, the molecular basis for these differences remains largely unknown. We previously reported that there exist differentially expressed miRNAs (DEMs) in the left and right kidneys of normal mice. Here, we identified the DEMs in the left and right eyes, lungs, and testes of normal mice via RNA sequencing. As a result, we identified 26 DEMs in eyes, with 23 higher and 3 lower in the left eyes compared with right eyes; 21 DEMs in lungs, with 15 higher and 6 lower in the left lungs compared with right lungs; and 54 DEMs in testes, with 6 higher and 48 lower in the left testes compared with right testes. Ten microRNAs (miRNAs) were further examined by quantitative PCR assays, and seven of these were confirmed. In addition, correlation analysis was performed between paired organ miRNA expressions and diverse body fluid miRNA expressions. Finally, we explored the functions and networks of DEMs and performed biological process and pathway enrichment analysis of target genes for DEMs, providing insights into the physiological and pathophysiological differences between the two entities of paired organs.

Female reproductive cycle, also known as menstrual cycle or estrous cycle in primate or non-primate mammals, respectively, dominates the reproductive processes in non-pregnant state. However, in addition to reproductive tissues, reproductive cycle could also perform global regulation because the receptors of two major female hormones fluctuating throughout the cycle, estrogen and progesterone, are widely distributed. Therefore, a multi-tissue gene expression landscape is in continuous demand for better understanding the systemic changes during the reproductive cycle but remains largely undefined. Here we delineated a transcriptomic landscape covering 15 tissues of C57BL/6J female mice in two phases of estrous cycle, estrus and diestrus, by RNA-sequencing. Then, a number of genes, pathways, and transcription factors involved in the estrous cycle were revealed. We found the estrous cycle could widely regulate the neuro-functions, immuno-functions, blood coagulation and so on. And behind the transcriptomic alteration between estrus and diestrus, 13 transcription factors may play important roles. Next, bioinformatics modeling with 1,263 manually curated gene signatures of various physiological and pathophysiological states systematically characterized the beneficial/deleterious effects brought by estrus/diestrus on individual tissues. We revealed that the estrous cycle has a significant effect on cardiovascular system (aorta, heart, vein), in which the anti-hypertensive pattern in aorta induced by estrus is one of the most striking findings. Inspired by this point, we validated that two hypotensive drugs, felodipine and acebutolol, could exhibit significantly enhanced efficacy in estrus than diestrus by mouse and rat experiments. Together, this study provides a valuable data resource for investigating reproductive cycle from a transcriptomic perspective, and presents models and clues for investigating precision medicine associated with reproductive cycle.

The sex chromosomes play central roles in determining the sex of almost all of the multicellular organisms. It is well known that meiosis in mammalian spermatogenesis produces ~50% Y- and ~50% X-chromosome-bearing sperm, a 1:1 ratio. Here we first reveal that the X-chromosome-encoded miRNAs show lower expression levels in the left testis than in the right testis in healthy mice using bioinformatics modeling of miRNA-sequencing data, suggesting that the Y:X ratio could be unbalanced between the left testis and the right testis. We further reveal that the Y:X ratio is significantly elevated in the left testis but balanced in the right testis using flow cytometry. This study represents the first time the biased Y:X ratio in the left testis but not in the right testis is revealed.