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Sex-dependent gene regulatory networks of the heart rhythm

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Abstract

Expression level, control, and intercoordination of 66 selected heart rhythm determinant (HRD) genes were compared in atria and ventricles of four male and four female adult mice. We found that genes encoding various adrenergic receptors, ankyrins, ion channels and transporters, connexins, cadherins, plakophilins, and other components of the intercalated discs form a complex network that is chamber dependent and differs between the two sexes. In addition, most HRD genes in atria had higher expression in males than in females, while in ventricles, expression levels were mostly higher in females than in males. Moreover, significant chamber differences were observed between the sexes, with higher expression in atria than ventricles for males and higher expression in ventricles than atria for females. We have ranked the selected genes according to their prominence (new concept) within the HRD gene web defined as extent of expression coordination with the other web genes and stability of expression. Interestingly, the prominence hierarchy was substantially different between the two sexes. Taken together, these findings indicate that the organizational principles of the heart rhythm transcriptome are sex dependent, with the newly introduced prominence analysis allowing identification of genes that are pivotal for the sexual dichotomy.

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Acknowledgments

The research was supported by the Award Number R01HL092001 (DAI) from the National Heart, Lung, and Blood Institute (NHLBI). The content is solely the responsibility of the authors and does not necessarily represent the NHLBI official views.

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Authors and Affiliations

  1. Dominick P Purpura Department of Neuroscience, Albert Einstein College of Medicine, 1300 Morris Park Ave, Kennedy Center, Room 713, New York, NY, 10461, USA

    D. A. Iacobas, S. Iacobas, N. Thomas & D. C. Spray

  2. Department of Medicine (Cardiology), Albert Einstein College of Medicine, New York, NY, USA

    D. C. Spray

  3. Dominick P Purpura Department of Neuroscience, Albert Einstein College of Medicine, 1300 Morris Park Ave, Kennedy Center, Room 840, New York, NY, 10461, USA

    D. C. Spray

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  1. D. A. Iacobas
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  2. S. Iacobas
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Correspondence to D. A. Iacobas.

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Supplementary Table 1

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Supplementary Figure 1

Independently expressed HRD gene pairs in atria and ventricles of adult male and female mice. Note the sex and chamber differences in the significant expression decoupling of the selected genes. Yellow background for Gja5 in male ventricles and Scn5a in female atria indicates that these genes were excluded from the analysis in the indicated samples. (GIF 243 kb)

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Iacobas, D.A., Iacobas, S., Thomas, N. et al. Sex-dependent gene regulatory networks of the heart rhythm. Funct Integr Genomics 10, 73–86 (2010). https://doi.org/10.1007/s10142-009-0137-8

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