The Core Circadian Clock Factor, Bmal1, Transduces Sex-specific Differences in Both Rhythmic and Nonrhythmic Gene Expression in the Mouse Heart. The Core Circadian Clock Factor, Bmal1, Transduces Sex-specific Differences in Both Rhythmic and Nonrhythmic Gene Expression in the Mouse Heart

Sexual dimorphism in mammals, including humans and laboratory rodents, has primarily been attributed to hormonal and sex chromosomal differences. Accumulating evidence now suggests that circadian rhythms also contribute to sexual dimorphism in cardiac physiology and cardiovascular diseases. Here, we show that the circadian transcriptome of the mouse heart exhibits sexual dimorphism. We determined that female hearts express significantly more rhythmically expressed genes (REGs) and that the temporal distribution of the REGs was different between males and females. In addition, the overlap in genes and functional pathways were modest between males and females. All aspects of the sexual dimorphism in the circadian transcriptome was significantly diminished with cardiomyocyte specific loss of the core clock gene, Bmal1. Analysis of all differentially expressed genes (DEGs) between males and females showed that differential expression between sexes was largely diminished with loss of cardiomyocyte Bmal1. We conclude that cardiomyocyte specific Bmal1, and likely the core clock mechanism, plays a vital role in conferring a sexually dimorphic program of gene expression in the adult mouse heart. Overall design: To investigate the role of BMAL1 in the sex differences of the heart circadian transcriptome in mice, we generated an inducible cardiomyocyte specific BMAL1 knockout (icsBmal1 KO) mouse.

包括人类与实验啮齿类在内的哺乳动物的性别二态性，此前主要被归因于激素与性染色体差异。如今越来越多的研究证据表明，昼夜节律同样参与调控心脏生理学与心血管疾病中的性别二态性。本研究证实，小鼠心脏的昼夜转录组存在性别二态性。我们发现，雌性心脏的节律表达基因（rhythmically expressed genes, REGs）数量显著更多，且这类基因的时间分布模式在雌雄个体间存在差异。此外，雌雄个体间的基因与功能通路重叠程度较低。当心肌细胞特异性缺失核心时钟基因Bmal1后，昼夜转录组的所有性别二态性特征均显著减弱。对雌雄个体间全部差异表达基因（differentially expressed genes, DEGs）的分析显示，随着心肌细胞Bmal1的缺失，性别间的表达差异大幅减弱。本研究由此得出结论：心肌细胞特异性的Bmal1，以及大概率核心时钟机制，在成年小鼠心脏的性别二态性基因表达程序中发挥至关重要的作用。实验整体设计：为探究BMAL1在小鼠心脏昼夜转录组性别差异中的作用，我们构建了可诱导型心肌细胞特异性BMAL1敲除（inducible cardiomyocyte specific BMAL1 knockout, icsBmal1 KO）小鼠模型。