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. 2025 Feb 12;6(1):zqae053.
doi: 10.1093/function/zqae053.

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

Xiping Zhang  1 , Spencer B Procopio  1 , Haocheng Ding  2 , Maya G Semel  1 , Elizabeth A Schroder  3   4 , Mark R Viggars  1 , Tanya S Seward  3 , Ping Du  1 , Kevin Wu  1 , Sidney R Johnson  3 , Abhilash Prabhat  3 , David J Schneider  3 , Isabel G Stumpf  3 , Ezekiel R Rozmus  3 , Zhiguang Huo  2 , Brian P Delisle  3 , Karyn A Esser  1
Affiliations

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

Xiping Zhang et al. Function (Oxf). .

Abstract

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.

Keywords: brain and muscle ARNT-like 1; cardiomyocyte; circadian rhythms; sex differences.

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Conflict of interest statement

KAE holds the position of Editorial Board Member for Function and is blinded from reviewing or making decisions for the manuscript.

Figures

Graphical Abstract
Graphical Abstract
Figure 1.
Figure 1.
Male and female core circadian clock expression and circadian transcriptomes. (A) Core clock gene expression in vehicle-treated mice (n = 2/timepoint). (B) Venn diagram of REGs comparison between male and female vehicle hearts. (C) Heatmap of z-scored male-specific, female-specific, and shared REGs over 48 hours in vehicle-treated mouse hearts.
Figure 2.
Figure 2.
Comparison of circadian transcriptome between male and female mouse heart. (A) Enriched biological pathways. The bubble plot shows representative enriched pathways. Bubble size indicates the number of REGs enriched. (B) Phase distribution of shared male and female mouse heart REGs. (C) Phase distribution of male-specific and female-specific REGs.
Figure 3.
Figure 3.
The temporal distribution of biological pathways. Phase distribution of enriched biological pathways of male hearts (A) and female hearts (B) in 6 bins by circular plot. (C) Enriched biological pathways. The phase distribution of REGs was shown on top of the bubble plot. Each column represents the pathways enriched in each peak of the distribution (female peak from hours 4-8: F4-8, male peak from hours 8-12: M8-12, female peak from hours 16-20: F16-20, male peak from hours 20-24: M20-24). The bubble plot shows representative enriched pathways. Bubble size indicates the number of REGs enriched.
Figure 4.
Figure 4.
Significant changes to circadian transcriptome in male and female iCS Bmal1 KO mouse hearts. (A) Venn diagram of REGs comparison between the male vehicle and iCS Bmal1 KO. (B) Heatmap of z-scored REGs expression over 48 hours of male vehicle-specific, iCS Bmal1 KO-specific, and shared REGs. (C) Comparison of the phase distribution of REGs over 24 hours between the male vehicle and iCS Bmal1 KO. (D) Venn diagram of REGs comparison between the female vehicle and iCS Bmal1 KO REGs (E) Heatmap of z-scored REGs over 48 hours of female vehicle-specific, iCS Bmal1 KO-specific, and shared REGs. (F) Comparison of the phase distribution of REGs over 24 hours between the female vehicle and iCS Bmal1 KO.
Figure 5.
Figure 5.
Comparison of male and female iCS Bmal1 KO circadian transcriptomes. (A) Venn diagram of REGs comparison between male and female iCS Bmal1 KO hearts. (B) Enriched biological pathways. The bubble plot shows representative enriched pathways. Bubble size indicates the number of REGs enriched. (C) Comparison of the phase distribution of shared REGs in male and female iCS Bmal1 KO hearts. (D) Comparison of the phase distribution of sex-specific REGs of male and female iCS Bmal1 KO.
Figure 6.
Figure 6.
Analysis of DEGs and transcription factors between sexes of vehicle and iCS Bmal1 KO hearts. (A) Bar graph of differential gene expression between male and female heart transcriptomes before and post-iCS Bmal1 knockout. Each bar is colored to represent the proportion of genes more highly expressed in each group. (B) Pathway analysis of DEGs upregulated in male and female vehicle-treated hearts. (C) Pathway analysis of DEGs upregulated in male (no significantly enriched pathways) and female iCS Bmal1 KO hearts. (D-E) Heatmap of z-score normalized expression averaged over 48 hours in all 4 genotypes, including male vehicle, female vehicle, male iCS Bmal1 KO, and female iCS Bmal1 KO of (D) nuclear receptors and (E) cardiac transcription factors (n = 24/group).
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