Skip to main content
SpringerLink
Log in

Epigenetic Activation of Ribosomal Cistrons in Chromatids of Acrocentric Chromosome 15 in Lung Cancer

  • Published:
Cytology and Genetics Aims and scope Submit manuscript

Abstract

After the Human Genome Project was declared complete, the strategic focus area of contemporary genetics shifted towards functional genomics whose research sphere comprises, among others, the study of noncoding DNA regions. The noncoding regions are located in heterochromatin. The functions of heterochromatin remain so far, to a considerable degree, unclear. The telomeres of the short arm of each human acrocentric chromosome (13, 14, 15, 21, 22) have satellite strands consisting of heterochromatin and are called nucleolar organizer regions (NORs). Human NORs contain from 250 to 670 copies of ribosomal RNA (rRNA) genes and only 50% of these copies are transcribed. Satellite strands in the chromatids of some acrocentric chromosomes are bound, forming “satellite associations” (SAs), which are always transcriptionally active. The phenomenon of SAs is a highly specific indicator for the structure and function of the nucleolus within the preceding interphase. In cancer, rDNA in the human genome may change. In this study, the epigenetic variability of ribosomal cistrons in lung cancer (LC) has been determined. It has been found that the frequency of chromatid SAs per cell was significantly higher (p < 0.05) in patients with LC (1.76 ± 0.08) than the analogous indicator in clinically healthy persons aged from 22 to 45 years (the control group) (1.35 ± 0.03). The associative activity in the chromatids of chromosome 15 group was lower (p < 0.01) than the activity in chromatids of other chromosomes. In contrast to the control group, the chromatids of chromosome 15 in the LC patients showed higher activity (p < 0.05) of inclusion into associations than chromatids of other acrocentric chromosomes, which corresponded to the order: 15 > 13 = 14 > 21 > 22. A similar phenomenon was observed for the associations of chromatids of homologous chromosomes (15:15) in patients with LC, which significantly exceeded the indicator for this type of SA in healthy middle-aged individuals (p < 0.001). The results have shown that the differential activity of satellite strands in the chromatids of chromosome 15 in patients with LC is characterized by epigenetic variability, which underlines the importance of studying SAs in terms of diagnosis and treatment strategy. The study of epigenetic variability in the activity of ribosomal cistrons in acrocentric chromatids in pathologies is a new medical area aiming at the diagnosis of diseases and determining new treatment strategies in the future.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2.
Fig. 3.

Similar content being viewed by others

REFERENCES

  1. Baranov, V. and Kuznecova, T., Cytogenetics of Human Embryonic Development, Leningrad: Nauka, 2006, pp. 3–329.

    Google Scholar 

  2. Bartova, E., Structure and epigenetics nucleoli compared with an unusual nucleola compartments, J. Histochem. Cytochem., 2015, vol. 58, pp. 391–403.

    Article  Google Scholar 

  3. Caudron-Herger, M. and Diederichs, S., Mitochondrial mutations in human cancer: duration of translation, RNA Biol., 2018, vol. 15, pp. 62–69.

    Article  Google Scholar 

  4. Caudron-Herger, M., Pankert, T., Seiler, J., et al., Alu element-containing RNAs maintain nucleolar structure and function, EMBO J., 2015, vol. 34, pp. 2758–2774.

    Article  CAS  Google Scholar 

  5. Cong, R., Das, S., Ugrinova, I., et al., Interaction of nucleolin with ribosomal RNA genes and its role in RNA polymerase 1 transcription, Nucleic Acids Res., 2012, vol. 19, pp. 9441–9454.

    Article  Google Scholar 

  6. Donat, G., Montanaro, L., and Derenzini, M., Ribosome biogenesis and control of cell proliferation: p53 is not alone, Cancer Res., 2012, vol 72l, pp. 1602–1607.

    Article  Google Scholar 

  7. Ginisty, H., Sicard, H., Roger, B., et al., Structure and functions of nucleolin, J. Cell Sci., 1999, vol. 12, pp. 761–772.

    Article  Google Scholar 

  8. Grummt, I. and Pikaard, C., Epigenetic mechanisms controlling RNA polymerase I transcription, Nat. Rev. Mol. Cell Biol., 2003, vol. 4, pp. 641–649.

    Article  CAS  Google Scholar 

  9. Hirota, K., Miyoshi, T., and Kugou, K., Stepwise chromatin remodeling by a cascade of transcription initiation of non-coding RNA, Nature, 2008, vol. 456, pp. 130–134.

    Article  CAS  Google Scholar 

  10. Horn, L. and Lovely, C., Neoplasms of the lung, in Harrison’s Principles of Internal Medicine, Jameson, J.L., Eds., 20th ed., 2018, chapter 74.

    Google Scholar 

  11. Kadotani, T., Watanabe, Y., and Makino, S., Chromosome study in aging, Int. J. Hum. Genet., 2002, vol. 2, pp. 5–9.

    Article  Google Scholar 

  12. Kim, J., Dilthey, A., Nagaraja, R., et al., Variation in human chromosome 21 ribosomal RNA gene is characterized by TAR cloning and long-read sequencing, Nucleic Acids Res., 2018, vol. 46, pp. 6712–6725.

    Article  CAS  Google Scholar 

  13. Lezhava, T., Human Chromosomes and Aging: From 80 to 114 Years, New York: Nova Science Publisher, 2006, pp. 3–177.

    Google Scholar 

  14. Lezhava, T., Jokhadze, T., and Monaselidze, J., The functioning of “aged” heterochromatin, in Senescence, Nagata, T., Ed., Intech Open Science, 2012, chapter 26, pp. 631–664.

    Google Scholar 

  15. Lezhava, T., Buadze, T., Jokhadze, T., et al., Normalization of epigenetic change in the genome by peptide bioregulator (Ala-Glu-Asp-Glu) in pulmonary tuberculosis, Int. J. Pept. Res. Ther., 2019, vol. 25, pp. 555–563.

    Article  CAS  Google Scholar 

  16. Lezhava, T., Buadze, T., Monaselidze, J., et al., Epigenetic changes of activity of the ribosomal cistrons of human acrocentric chromatids in fetuses, middle-aged (22–45 years) and old individuals (80–106 years), Cytol. Genet., 2020, vol. 54, pp. 233–242.

    Article  Google Scholar 

  17. Malinovskaya, E., Ershova, E., Golimbet, V., et al., Copy number of human ribosomal genes with aging: unchanged mean, but narrowed range and decreased variance in elderly group, Front. Genet., 2018. https://doi.org/10.3389/fgene.2018.00306

  18. Mattick, J. and Mehler, M., RNA editing, DNA recoding and the evolution of human cognition, Trends Neurosci., 2008, vol. 31, pp. 227–233.

    Article  CAS  Google Scholar 

  19. Mayer, C., Neubert, M., and Grummt, I., The structure of NoRC-associated RNA is crucial for targeting the chromatin remodelling complex NoRC to the nucleolus, EMBO Rep., 2008, vol. 9, pp. 774–780.

    Article  CAS  Google Scholar 

  20. Mazin, A., Suicidal function of DNA methylation in age-related genome disintegration, Ageing Res. Rev., 2009, vol. 8, no. 4, pp. 314–327.

    Article  CAS  Google Scholar 

  21. Nemeth, A. and Langst, G., Genome organization in and around the nucleolus, Trends Genet., 2011, vol. 27, pp. 149–156.

    Article  CAS  Google Scholar 

  22. Olson, M., The Nucleolus, Spinger Science LLC, 2011, pp. 105–278.

    Google Scholar 

  23. Pankaj, K. and Desai, B., Frequency of satellite associations of acrocentric chromosomes in oral squamous cell carcinoma patients after 5-FU and cisplatin treatments, Int. J. Mol. Med. Sci., 2016, vol. 6, pp. 1–5.

    Google Scholar 

  24. Porokhovnik, L. and Gerton, J., Ribosomal DNA-connecting ribosome biogenesis and chromosome biology, Chromosome Res., 2019, vol. 27, pp. 1–3.

    Article  CAS  Google Scholar 

  25. Porokhovnik, L. and Lyapunova, N., Dosage effects of human ribosomal genes (rDNA) in health and disease, Chromosome Res., 2019, vol. 27, pp. 5–17.

    Article  CAS  Google Scholar 

  26. Prokofeva-Belgovskay, A., Heterochromatin Regions of Chromosomes, Moscow: Nauka, 1986, pp. 3–431.

    Google Scholar 

  27. Santoro, R. and Grummt, I., Epigenetic mechanism of rRNA gene silencing: temporal order of NoRC mediated histone modification, chromatin remodeling, and DNA methylation, Mol. Cell Biol., 2005, vol. 25, pp. 2539–2546.

    Article  CAS  Google Scholar 

  28. Savku, R. and Olson, M., Protein B23 endoribonuclease could play a role in pre-rRNA processing, Nucleic Acids Res., 1998, vol. 26, pp. 4508–4515.

    Article  Google Scholar 

  29. Schmitz, K., Schmit, N., Hoffman-Robrer, U., et al., TAF12 recruits Gadd45a and the nucleotide excision repair complex to the promoter of rRNA genes leading to active DNA demethylation, Mol. Cell, 2009, vol. 33, pp. 344–353.

    Article  CAS  Google Scholar 

  30. Shen, H., Zhu, M., and Wang, C., Precision oncology of lung cancer: genetic and genomic differences in Chinese population, NPJ Precis. Onc., 2019. https://doi.org/10.1038/s41698-019-0086-1

    Book  Google Scholar 

  31. Sluis, M., Vuuren, C., Mangan, H., et al., NORs on human acrocentric chromosome p-arms are active by default and can associate with nucleoli independently of rDNA, Proc. Natl. Acad. Sci. U. S. A., 2020, vol. 117, pp. 10368–10377.

    Article  Google Scholar 

  32. Storck, S., Shukla, M., Dimitrov, S., et al., Functions of the histone chaperone nucleolin in diseases, Biochemistry, 2007, vol. 41, pp. 25–44.

    Google Scholar 

  33. Valori, V., Tus, K., Laukaitis, C., et al., Human rDNA copy number is unstable in metastatic breast cancers, Epigenetics, 2020, vol. 15, pp. 85–106.

    Article  Google Scholar 

Download references

Funding

The study was supported by Javakhishvili Tbilisi State University.

Author information

Authors and Affiliations

  1. Department of Genetics, Ivane Javakhishvili Tbilisi State University, 0128, Tbilisi, Georgia

    T. Lezhava, T. Buadze, N. Mikaia, T. Jokhadze, T. Sigua & M. Gaiozishvili

  2. Laboratory of Oncology, Todua Medical Center, Tbilisi, Georgia

    T. Melkadze

Authors
  1. T. Lezhava
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T. Buadze
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. N. Mikaia
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. T. Jokhadze
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. T. Sigua
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M. Gaiozishvili
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. T. Melkadze
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Pr. T. Lezhava designed the plan for the study. Pr. T. Jokhadze, Dr. T. Buadze, and Dr. M. Gaiiozishvili performed the experimental part of the study. The postgraduates T. Sigua, N. Mikaia, and T. Melkadze performed technical procedures.

Corresponding author

Correspondence to T. Lezhava.

Ethics declarations

Conflict of interest. The authors declare that they have no conflict of interest.

Statement of compliance with standards of research involving humans as subjects. The protocol of the study was approved by the Committee on Ethics of Tbilisi State Medical University (TbSMU, Georgia), and all persons participating in the study gave their written informed consent.

Additional information

Translated by N. Tarasyuk

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lezhava, T., Buadze, T., Mikaia, N. et al. Epigenetic Activation of Ribosomal Cistrons in Chromatids of Acrocentric Chromosome 15 in Lung Cancer. Cytol. Genet. 55, 491–497 (2021). https://doi.org/10.3103/S0095452721050042

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.3103/S0095452721050042

Keywords:

Search

Navigation