Zhang Xiping, Procopio Spencer B, Ding Haocheng, Semel Maya G, Schroder Elizabeth A, Viggars Mark R, Seward Tanya S, Du Ping, Wu Kevin, Johnson Sidney R, Prabhat Abhilash, Schneider David J, Stumpf Isabel G, Rozmus Ezekiel R, Huo Zhiguang, Delisle Brian P, Esser Karyn A
Department of Physiology and Aging, University of Florida, Gainesville, FL 32610, USA.
Department of Biostatics, University of Florida, Gainesville, FL 32611, USA.
Function (Oxf). 2025 Feb 12;6(1). doi: 10.1093/function/zqae053.
It has been well established that cardiovascular diseases exhibit significant differences between sexes in both preclinical models and humans. In addition, there is growing recognition that disrupted circadian rhythms can contribute to the onset and progression of cardiovascular diseases. However, little is known about sex differences between the cardiac circadian clock and circadian transcriptomes in mice. Here, we show that the core clock genes are expressed in common in both sexes, but the cardiac circadian transcriptome is very sex-specific. Hearts from female mice expressed significantly more rhythmically expressed genes (REGs) than male hearts, and the temporal distribution of REGs was distinctly different between sexes. To test the contribution of the circadian clock in sex-specific gene expression in the heart, we knocked out the core circadian clock factor Bmal1 in adult cardiomyocytes. The sex differences in the circadian transcriptomes were significantly diminished with cardiomyocyte-specific loss of Bmal1. Surprisingly, loss of cardiomyocyte Bmal1 also resulted in a roughly 8-fold reduction in the number of all differentially expressed genes between male and female hearts. We highlight sex-specific changes in several cardiac-specific transcription factors, including Gata4, Nkx2-5, and Tbx5. While there is still much to learn, we conclude that cardiomyocyte-specific Bmal1 is vital in conferring sex-specific gene expression in the adult mouse heart.
心血管疾病在临床前模型和人类中均表现出显著的性别差异，这一点已经得到充分证实。此外，人们越来越认识到昼夜节律紊乱会促进心血管疾病的发生和发展。然而，关于小鼠心脏昼夜节律钟和昼夜转录组之间的性别差异，我们知之甚少。在此，我们表明核心生物钟基因在两性中均有共同表达，但心脏昼夜转录组具有很强的性别特异性。雌性小鼠心脏中节律性表达基因（REGs）的表达明显多于雄性心脏，且REGs的时间分布在两性之间明显不同。为了测试昼夜节律钟对心脏性别特异性基因表达的作用，我们在成年心肌细胞中敲除了核心昼夜节律钟因子Bmal1。随着心肌细胞特异性缺失Bmal1，昼夜转录组中的性别差异显著减小。令人惊讶的是，心肌细胞Bmal1的缺失还导致雄性和雌性心脏之间所有差异表达基因的数量减少了约8倍。我们强调了几种心脏特异性转录因子的性别特异性变化，包括Gata4、Nkx2-5和Tbx5。尽管仍有许多有待了解的地方，但我们得出结论，心肌细胞特异性Bmal1对于成年小鼠心脏中性别特异性基因表达至关重要。
