A multi-tissue transcriptomic landscape of female mice in estrus and diestrus provides clues for precision medicine

Yiran Zhou; Han Yan; Wenjun Liu; Chengqing Hu; Yuan Zhou; Ruya Sun; Yida Tang; Chao Zheng; Jichun Yang; Qinghua Cui

doi:10.3389/fcell.2022.983712

A multi-tissue transcriptomic landscape of female mice in estrus and diestrus provides clues for precision medicine

Front Cell Dev Biol. 2022 Dec 16:10:983712. doi: 10.3389/fcell.2022.983712. eCollection 2022.

Authors

Yiran Zhou^{1

2

3}, Han Yan⁴, Wenjun Liu², Chengqing Hu², Yuan Zhou^{1

2}, Ruya Sun^{1

2}, Yida Tang⁵, Chao Zheng⁴, Jichun Yang², Qinghua Cui^{1

2}

Affiliations

¹ Department of Biomedical Informatics, Center for Noncoding RNA Medicine, MOE Key Lab of Cardiovascular Sciences, School of Basic Medical Sciences, Peking University, Beijing, China.
² 2 Department of Physiology and Pathophysiology, Center for Noncoding RNA Medicine, MOE Key Lab of Cardiovascular Sciences, School of Basic Medical Sciences, Peking University, Beijing, China.
³ Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Peking University, Beijing, China.
⁴ Department of Endocrinology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
⁵ Department of Cardiology, MOE Key Lab of Cardiovascular Sciences, Peking University Third Hospital, Beijing, China.

Abstract

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.

Keywords: RNA-sequencing; estrous cycle; hypertension; reproductive cycle; systems biology.