Skip to main content

Epigenetic mechanisms of peptidergic regulation of gene expression during aging of human cells

Abstract

Expression levels of genes encoding specific transcription factors and other functionally important proteins vary upon aging of pancreatic and bronchial epithelium cell cultures. The peptides KEDW and AEDL tissue-specifically affect gene expression in pancreatic and bronchial cell cultures, respectively. It is established in this work that the DNA methylation patterns of the PDX1, PAX6, NGN3, NKX2-1, and SCGB1A1 gene promoter regions change upon aging in pancreatic and bronchial cell cultures in correlation with variations in their expression levels. Thus, stable changes in gene expression upon aging of cell cultures could be caused by changes in their promoter methylation patterns. The methylation patterns of the PAX4 gene in pancreatic cells as well as those of the FOXA1, SCGB3A2, and SFTPA1 genes in bronchial cells do not change upon aging and are unaffected by peptides, whereas their expression levels change in both cases. The promoter region of the FOXA2 gene in pancreatic cells contains a small number of methylated CpG sites, their methylation levels being affected by cell culture aging and KEDW, though without any correlation with gene expression levels. The promoter region of the FOXA2 gene is completely unmethylated in bronchial cells irrespective of cell culture age and AEDL action. Changes in promoter methylation might be the cause of age- and peptide-induced variations in expression levels of the PDX1, PAX6, and NGN3 genes in pancreatic cells and NKX2-1 and SCGB1A1 genes in bronchial cells. Expression levels of the PAX4 and FOXA2 genes in pancreatic cells and FOXA1, FOXA2, SCGB3A2, and SFTPA1 genes in bronchial cells seem to be controlled by some other mechanisms.

This is a preview of subscription content, access via your institution.

Abbreviations

AEDL:

peptide H-Ala-Glu-Asp-Leu-OH

bp:

base pair

CGI:

CpG-island

KEDW:

peptide H-Lys-Glu-Asp-Trp-NH2

TIS:

transcription initiation site

References

  1. 1.

    Khavinson, V. Kh., Durnova, A. O., Polyakova, V. O., Tolibova, G. H., Linkova, N. S., Kvetnoy, I. M., and Tarnovskaya, S. I. (2013) Effects of pancragen on the differentiation of pancreatic cells during their ageing, Bull. Exp. Biol. Med., 154, 501–504.

    Article  CAS  PubMed  Google Scholar 

  2. 2.

    Khavinson, V. Kh., Gapparov, M. M.-G., Sharanova, N. E., Vasilyev, A. V., and Ryzhak, G. A. (2010) Study of biological activity of Lys-Glu-Asp-Trp-NH2 endogenous tetrapeptide, Bull. Exp. Biol. Med., 149, 351–353.

    Article  CAS  PubMed  Google Scholar 

  3. 3.

    Korkushko, O. V., Khavinson, V. Kh., Shatilo, V. B., and Antonyk-Sheglova, I. A. (2011) Peptide geroprotector from the pituitary gland inhibits rapid aging of elderly people: results of 15-year follow-up, Bull. Exp. Biol. Med., 151, 366–369.

    Article  CAS  PubMed  Google Scholar 

  4. 4.

    Korkushko, O. V., Khavinson, V. Kh., Shatilo, V. B., Antonyk-Sheglova, I. A., and Bondarenko, E. V. (2011) Prospects of using pancragen for correction of metabolic disorders in elderly people, Bull. Exp. Biol. Med., 151, 454–456.

    Article  CAS  PubMed  Google Scholar 

  5. 5.

    Khavinson, V. Kh., Tendler, S. M., Vanyushin, B. F., Kasyanenko, N. A., Kvetnoy, I. M., Linkova, N. S., Ashapkin, V. V., Polyakova, V. O., Basharina, V. S., and Bernadotte, A. (2014) Peptide regulation of gene expression and protein synthesis in bronchial epithelium, Lung, 192, 781–791.

    Article  CAS  PubMed  Google Scholar 

  6. 6.

    Khavinson, V. Kh., Linkova, N. S., Polyakova, V. O., Kheifets, O. V., Tarnovskaya, S. I., and Kvetnoy, I. M. (2012) Peptides tissue-specifically stimulate cell differentiation during their aging, Bull. Exp. Biol. Med., 153, 148–151.

    Article  CAS  PubMed  Google Scholar 

  7. 7.

    Pogribny, I. P., and Vanyushin, B. F. (2010) Age-related genomic hypomethylation, in Epigenetics of Aging (Tollefsbol, T. O., ed.) Springer Science+Business Media, N. Y., pp. 11–27.

    Chapter  Google Scholar 

  8. 8.

    Schumacher, A. (2011) Aging epigenetics, in Handbook of Epigenetics. The New Molecular and Medical Genetics (Tollefsbol, T. O., ed.) Elsevier Inc., Amsterdam, pp. 405–422.

    Chapter  Google Scholar 

  9. 9.

    Bell, J. T., Tsai, P.-C., Yang, T.-P., Pidsley, R., Nisbet, J., Glass, D., Mangino, M., Zhai, G., Zhang, F., Valdes, A., Shin, S. Y., Dempster, E. L., Murray, R. M., Grundberg, E., Hedman, A. K., Nica, A., Small, K. S., Dermitzakis, E. T., McCarthy, M. I., Mill, J., Spector, T. D., and Deloukas, P. (2012) Epigenome-wide scans identify differentially methylated regions for age and age-related phenotypes in a healthy ageing population, PLoS Genet., 8, e1002629; DOI: 10.1371/journal.pgen.1002629.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. 10.

    Day, K., Waite, L. L., Thalacker-Mercer, A., West, A., Bamman, M. M., Brooks, J. D., Myers, R. M., and Absher, D. (2013) Differential DNA methylation with age displays both common and dynamic features across human tissues that are influenced by CpG landscape, Genome Biol., 14, R102.

    Article  PubMed Central  PubMed  Google Scholar 

  11. 11.

    Hannum, G., Guinney, J., Zhao, L., Zhang, L., Hughes, G., Sadda, S., Klotzle, B., Bibikova, M., Fan, J. B., Gao, Y., Deconde, R., Chen, M., Rajapakse, I., Friend, S., Ideker, T., and Zhang, K. (2013) Genome-wide methylation profiles reveal quantitative views of human aging rates, Mol. Cell, 49, 359–367.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. 12.

    Florath, I., Butterbach, K., Mueller, H., Bewerunge-Hudler, M., and Brenner, H. (2014) Cross-sectional and longitudinal changes in DNA methylation with age: an epigenome-wide analysis revealing over 60 novel age-associated CpG sites, Hum. Mol. Genet., 23, 1186–1201.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. 13.

    Tusnady, G. E., Simon, I., Varadi, A., and Aranyi, T. (2005) BiSearch: primer-design and search tool for PCR on bisulfite treated genomes, Nucleic Acids Res., 33, e9.

    Article  PubMed Central  PubMed  Google Scholar 

  14. 14.

    Aranyi, T., Varadi, A., Simon, I., and Tusnady, G. E. (2006) The BiSearch web server, BMC Bioinformatics, 7, 431.

    Article  PubMed Central  PubMed  Google Scholar 

  15. 15.

    Grunau, C., Schattevoy, R., Mache, N., and Rosenthal, A. (2000) MethTools — a toolbox to visualize and analyze DNA methylation data, Nucleic Acids Res., 28, 1053–1058.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. 16.

    Lewin, J., Schmitt, A. O., Adorjan, P., Hildmann, T., and Piepenbrock, C. (2004) Quantitative DNA methylation analysis based on four-dye trace data from direct sequencing of PCR amplificates, Bioinformatics, 20, 3005–3012.

    Article  CAS  PubMed  Google Scholar 

  17. 17.

    Rakyan, V. K., Hildmann, T., Novik, K. L., Lewin, J., Tost, J., Cox, A. V., Andrews, T. D., Howe, K. L., Otto, T., Olek, A., Fischer, J., Gut, I. G., Berlin, K., and Beck, S. (2004) DNA methylation profiling of the human major histocompatibility complex: a pilot study for the human epigenome project, PLoS Biol., 2, e405.

    Article  PubMed Central  PubMed  Google Scholar 

  18. 18.

    Arda, H. E., Benitez, C. M., and Kim, S. K. (2013) Gene regulatory networks governing pancreas development, Devel. Cell, 25, 5–13.

    Article  CAS  Google Scholar 

  19. 19.

    Conrad, E., Stein, R., and Hunter, C. S. (2014) Revealing transcription factors during human pancreatic β cell development, Trends Endocrinol. Metab., 25, 407–414.

    Article  CAS  PubMed  Google Scholar 

  20. 20.

    Maeda, Y., Dave, V., and Whitsett, J. A. (2007) Transcriptional control of lung morphogenesis, Physiol. Rev., 87, 219–244.

    Article  CAS  PubMed  Google Scholar 

  21. 21.

    Illingworth, R. S., and Bird, A. P. (2009) CpG islands — “a rough guide”, FEBS Lett., 583, 1713–1720.

    Article  CAS  PubMed  Google Scholar 

  22. 22.

    Deaton, A. M., and Bird, A. (2011) CpG islands and the regulation of transcription, Genes Devel., 25, 1010–1022.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. 23.

    Jones, P. A. (2012) Functions of DNA methylation: islands, start sites, gene bodies and beyond, Nat. Rev. Genet., 13, 484–492.

    Article  CAS  PubMed  Google Scholar 

  24. 24.

    Smith, Z. D., and Meissner, A. (2013) DNA methylation: roles in mammalian development, Nat. Rev. Genet., 14, 204–220.

    Article  CAS  PubMed  Google Scholar 

  25. 25.

    Huntriss, J., Lorenzi, R., Purewal, A., and Monk, M. (1997) A methylation-dependent DNA-binding activity recognizing the methylated promoter region of the mouse Xist gene, Biochem. Biophys. Res. Commun., 235, 730–738.

    Article  CAS  PubMed  Google Scholar 

  26. 26.

    Han, H., Cortez, C. C., Yang, X., Nichols, P. W., Jones, P. A., and Liang, G. (2011) DNA methylation directly silences genes with non-CpG island promoters and establishes a nucleosome occupied promoter, Hum. Mol. Genet., 20, 4299–4310.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. 27.

    Gustems, M., Woellmer, A., Rothbauer, U., Eck, S. H., Wieland, T., Lutter, D., and Hammerschmidt, W. (2014) c-Jun/c-Fos heterodimers regulate cellular genes via a newly identified class of methylated DNA sequence motifs, Nucleic Acids Res., 42, 3059–3072.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. 28.

    Fedoreeva, L. I., Kireev, I. I., Khavinson, V. Kh., and Vanyushin, B. F. (2011) Penetration of short fluorescencelabeled peptides into the nucleus in HeLa cells and in vitro specific interaction of the peptides with deoxyribooligonucleotides and DNA, Biochemistry (Moscow), 76, 1210–1219.

    Article  Google Scholar 

  29. 29.

    Khavinson, V. Kh., Fedoreeva, L. I., and Vanyushin, B. F. (2011) Short peptides modulate the effect of endonucleases of wheat seedling, Doklady Biochem. Biophys., 437, 64–67.

    Article  CAS  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to V. V. Ashapkin.

Additional information

Published in Russian in Biokhimiya, 2015, Vol. 80, No. 3, pp. 374–388.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ashapkin, V.V., Linkova, N.S., Khavinson, V.K. et al. Epigenetic mechanisms of peptidergic regulation of gene expression during aging of human cells. Biochemistry Moscow 80, 310–322 (2015). https://doi.org/10.1134/S0006297915030062

Download citation

Key words

  • short peptides
  • DNA methylation
  • transcription
  • cell differentiation
  • pancreatic cell culture
  • bronchial cell culture
  • differentiation factors