pp 1–6 | Cite as

Network-based transcriptomic analysis reveals novel melatonin-sensitive genes in cardiovascular system

  • Ke Li
  • Fan Hu
  • Wan Xiong
  • Qing Wei
  • Fang-Fang LiuEmail author
Original Article



Heart disease is a major cause of mortality and disability worldwide. Melatonin is a neuroendocrine hormone and has been found to be protective in heart disease. However, the molecular basis underlying this cardioprotective effect is not fully understood. Here we aim to investigate melatonin-sensitive genes in cardiovascular system using public gene expression databases.


An innovative genomic analysis method, the weighted gene co-expression network analysis (WGCNA) combined with differential gene expression analysis, was used in this study. The algorithm was implemented in R/Bioconductor.


Using this method, we provide a comprehensive characterization of transcriptional profiles associated with melatonin treatment. We found that 357 differentially expressed genes (DEGs) were highly sensitive to melatonin in mouse myocardium. Enrichment analysis showed that these 357 genes were mostly related to GO:0051984 (positive regulation of chromosome segregation), GO:0016605 (PML body) and GO:0006281 (DNA repair). We further obtained 5 hub genes from the 357 DEGs, including Set, Dhx40, Scaf11, Cfh, and Nup43.


We identified numerous melatonin-sensitive genes and further identified five hub genes. The five novel genes are possibly associated with the myocardial benefits of melatonin.


Melatonin Transcriptomic analysis Network pharmacology WGCNA 



We thank the Tongji Medical Science Library for computer resources. We thank our collaborators at the Department of Pathophysiology at Huazhong University of Science and Technology for their assistance in the study.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with animals performed by any of the authors.

Supplementary material

12020_2019_1925_MOESM1_ESM.pdf (221 kb)
Supplementary data
12020_2019_1925_MOESM2_ESM.csv (5.5 mb)
Supplementary Table 4


  1. 1.
    F. Zannad, Rising incidence of heart failure demands action. Lancet 391(10120), 518–9 (2018). CrossRefGoogle Scholar
  2. 2.
    G. Favero, L. Franceschetti, B. Buffoli, M.H. Moghadasian, R.J. Reiter, L.F. Rodella, R. Rezzani, Melatonin: protection against age-related cardiac pathology. Ageing Res Rev. 35, 336–49 (2017). CrossRefGoogle Scholar
  3. 3.
    S. Tengattini, R.J. Reiter, D.X. Tan, M.P. Terron, L.F. Rodella, R. Rezzani, Cardiovascular diseases: protective effects of melatonin. J. Pineal Res. 44(1), 16–25 (2008). Google Scholar
  4. 4.
    A. Lochner, E. Marais, B. Huisamen, Melatonin and cardioprotection against ischaemia/reperfusion injury: what’s new? A review. J. Pineal Res. 65(1), e12490 (2018). CrossRefGoogle Scholar
  5. 5.
    P. Langfelder, S. Horvath, WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics 9, 559 (2008). CrossRefGoogle Scholar
  6. 6.
    M.E. Ritchie, B. Phipson, D. Wu, Y. Hu, C.W. Law, W. Shi, G.K. Smyth, limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 43(7), e47 (2015). CrossRefGoogle Scholar
  7. 7.
    I. Loiodice, A. Alves, G. Rabut, M. Van Overbeek, J. Ellenberg, J.B. Sibarita, V. Doye, The entire Nup107-160 complex, including three new members, is targeted as one entity to kinetochores in mitosis. Mol. Biol. Cell 15(7), 3333–44 (2004). CrossRefGoogle Scholar
  8. 8.
    G.T. Haskell, B.C. Jensen, L.A. Samsa, D. Marchuk, W. Huang, C. Skrzynia, C. Tilley, B.A. Seifert, E.A. Rivera-Munoz, B. Koller, K.C. Wilhelmsen, J. Liu, H. Alhosaini, K.E. Weck, J.P. Evans, J.S. Berg, Whole exome sequencing identifies truncating variants in nuclear envelope genes in patients with cardiovascular disease. Circ. Cardiovasc. Genet. 10(3) (2017).
  9. 9.
    M. Li, A. Makkinje, Z. Damuni, The myeloid leukemia-associated protein SET is a potent inhibitor of protein phosphatase 2A. J. Biol. Chem. 271(19), 11059–62 (1996)CrossRefGoogle Scholar
  10. 10.
    J. Heijman, M. Dewenter, A. El-Armouche, D. Dobrev, Function and regulation of serine/threonine phosphatases in the healthy and diseased heart. J. Mol. Cell. Cardiol. 64, 90–98 (2013). CrossRefGoogle Scholar
  11. 11.
    E.R. Lubbers, P.J. Mohler, Roles and regulation of protein phosphatase 2A (PP2A) in the heart. J. Mol. Cell. Cardiol. 101, 127–33 (2016). CrossRefGoogle Scholar
  12. 12.
    S.A. Rosales-Corral, D. Acuna-Castroviejo, A. Coto-Montes, J.A. Boga, L.C. Manchester, L. Fuentes-Broto, A. Korkmaz, S. Ma, D.X. Tan, R.J. Reiter, Alzheimer’s disease: pathological mechanisms and the beneficial role of melatonin. J. Pineal Res. 52(2), 167–202 (2012). CrossRefGoogle Scholar
  13. 13.
    P.O. Koh, Melatonin attenuates decrease of protein phosphatase 2A subunit B in ischemic brain injury. J. Pineal Res. 52(1), 57–61 (2012). CrossRefGoogle Scholar
  14. 14.
    T.B. Lin, M.C. Hsieh, C.Y. Lai, J.K. Cheng, H.H. Wang, Y.P. Chau, G.D. Chen, H.Y. Peng, Melatonin relieves neuropathic allodynia through spinal MT2-enhanced PP2Ac and downstream HDAC4 shuttling-dependent epigenetic modification of hmgb1 transcription. J. Pineal Res. 60(3), 263–76 (2016). CrossRefGoogle Scholar
  15. 15.
    K.C. Koeijvoets, S.P. Mooijaart, G.M. Dallinga-Thie, J.C. Defesche, E.W. Steyerberg, R.G. Westendorp, J.J. Kastelein, P.M. van Hagen, E.J. Sijbrands, Complement factor H Y402H decreases cardiovascular disease risk in patients with familial hypercholesterolaemia. Eur. Heart J. 30(5), 618–23 (2009). CrossRefGoogle Scholar
  16. 16.
    J.K. Pai, J.E. Manson, K.M. Rexrode, C.M. Albert, D.J. Hunter, E.B. Rimm, Complement factor H (Y402H) polymorphism and risk of coronary heart disease in US men and women. Eur. Heart J. 28(11), 1297–303 (2007). CrossRefGoogle Scholar
  17. 17.
    R. Parente, S.J. Clark, A. Inforzato, A.J. Day, Complement factor H in host defense and immune evasion. Cell Mol. Life Sci. 74(9), 1605–24 (2017). CrossRefGoogle Scholar
  18. 18.
    K.C.F. Lidani, T.L. Sandri, F.A. Andrade, L. Bavia, R. Nisihara, I.J. Messias-Reason, Complement Factor H as a potential atherogenic marker in chronic Chagas’ disease. Parasite Immunol. 40(7), e12537 (2018). CrossRefGoogle Scholar
  19. 19.
    J. Rebehmed, P. Revy, G. Faure, J.P. de Villartay, I. Callebaut, Expanding the SRI domain family: a common scaffold for binding the phosphorylated C-terminal domain of RNA polymerase II. FEBS Lett. 588(23), 4431–7 (2014). CrossRefGoogle Scholar
  20. 20.
    J. Xu, H. Wu, C. Zhang, Y. Cao, L. Wang, L. Zeng, X. Ye, Q. Wu, J. Dai, Y. Xie, Y. Mao, Identification of a novel human DDX40gene, a new member of the DEAH-box protein family. J. Hum. Genet. 47(12), 681–3 (2002). CrossRefGoogle Scholar
  21. 21.
    J.X. Jin, S. Lee, A. Taweechaipaisankul, G.A. Kim, B.C. Lee, Melatonin regulates lipid metabolism in porcine oocytes. J. Pineal Res. 62(2) (2017).
  22. 22.
    B. Zhang, S. Horvath, A general framework for weighted gene co-expression network analysis. Stat. Appl. Genet. Mol. Biol. 4, Article 17 (2005).
  23. 23.
    W. Zhao, P. Langfelder, T. Fuller, J. Dong, A. Li, S. Hovarth, Weighted gene coexpression network analysis: state of the art. J. Biopharm. Stat. 20(2), 281–300 (2010). CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Blood Transfusion, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanP. R. China
  2. 2.Department of Pathophysiology, School of Basic Medicine, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanP. R. China
  3. 3.The Institute of Brain Research, Collaborative Innovation Center for Brain ScienceHuazhong University of Science and TechnologyWuhanP. R. China
  4. 4.Department of Pathology, The Central Hospital of Wuhan, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanP. R. China

Personalised recommendations