Skip to main content
SpringerLink
Log in

Alternative promoters located in SGMS1 gene introns participate in regulation of its expression in human tissues

  • Cell Molecular Biology
  • Published:
Molecular Biology Aims and scope Submit manuscript

Abstract

Sphingomyelin synthase 1 (SMS1) is a vitally important enzyme responsible for the synthesis of sphingomyelin and diacylglycerol from phosphatidylcholine and ceramide in eukaryotic cells. Previously, we have investigated the structure of the human gene SGMS1 in detail and identified a lot of its transcripts. We have found mRNA isoforms that differ in their 5′-untranslated regions (UTRs) and encode a full-length protein. We have also detected the transcripts that arise from an alternative exon combination and comprise a coding region of the gene and a 3′-UTR. Computer analysis revealed that the synthesis of the transcripts differing in 5′-UTRs starts from different SGMS1 gene promoters. In the present study performed using the realtime PCR, we demonstrated that the contents of five alternative gene transcripts that differ in their 5′-UTRs is substantially dissimilar in the studied human tissues. The transcripts synthesized under the control of the distal promoter comprising exon 1 were the most abundant. The content of the transcripts comprising 5′-terminal exons, the synthesis of which is enabled by the promoters localized in the gene introns, is lower. Different contents of gene SGMS1 transcripts that differ in 5′-UTRs indicates that the use of certain alternative promoters is tissue-specific and, apparently, strictly regulated. The 5′-UTR structures of the SGMS1 gene transcripts controlled by alternative promoters differ significantly, which indicates that the gene functioning is regulated at the posttranscriptional level.

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

Similar content being viewed by others

References

  1. Tress M.L., Martelli P.L., Frankish A., Reeves G.A., Wesselink J.J., Yeats C., Óason P.L’., Albrecht M., Hegyi H., Giorgetti A., Raimondo D., Lagarde J., Laskowski R.A., López G., Sadowski M.I., Watson J.D., Fariselli P., Rossi I., Nagy A., Kai W., Størling Z., Orsini M., Assenov Y., Blankenburg H., Huthmacher C., Ramírez F., Schlicker A., Denoeud F., Jones P., Kerrien S., Orchard S., Antonarakis S.E., Reymond A., Birney E., Brunak S., Casadio R., Guigo R., Harrow J., Hermjakob H., Jones D.T., Lengauer T., A. Orengo C., Patthy L., Thornton J.M., Tramontano A., Valencia A. 2007. The implications of alternative splicing in the ENCODE protein complement. Proc. Natl. Acad. Sci. U. S. A. 104, 5495–5500.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Lee J.Y., Yeh I., Park J.Y., Tian B. 2007. PolyA-DB 2: mRNA polyadenylation sites in vertebrate genes. Nucleic Acids Res. 35, D165–D168.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Denoeud F., Kapranov P., Ucla C., Frankish A., Castelo R., Drenkow J., Lagarde J., Alioto T., Manzano C., Chrast J., Dike S., Wyss C., Henrichsen C.N., Holroyd N., Dickson M.C., Taylor R., Hance Z., Foissac S., Myers R.M., Rogers J., Hubbard T., Harrow J., Guigó R., Gingeras T.R., Antonarakis S.E., Reymond A. 2007. Prominent use of distal 5′ transcription start sites and discovery of a large number of additional exons in ENCODE regions. Genome Res. 17, 746–759.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Kimura K., Wakamatsu A., Suzuki Y., Ota T., Nishikawa T., Yamashita R., Yamamoto J.-I., Sekine M., Tsuritani K., Wakaguri H., Ishii S., Sugiyama T., Saito K., Isono Y., Irie R., Kushida N., Yoneyama T., Otsuka R., Kanda K., Yokoi T., Kondo H., Wagatsuma M., Murakawa K., Ishida S., Ishibashi T., Takahashi-Fujii A., Tanase T., Nagai K., Kikuchi H., Nakai K., Isogai T., Sugano S. 2006. Diversification of transcriptional modulation: Large-scale identification and characterization of putative alternative promoters of human genes. Genome Res. 16, 55–65.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Dergunova L.V., Vladychenskaia I.P., Polukarova L.G., Raevskaia N.M., Lelikova G.P., Limborskaia S.A. 1998. Features of the structure, expression and chromosomal mapping of the nucleotide sequences of Hmob3 and Hmob33, obtained from a human medulla oblongata cDNA library. Mol. Biol. (Moscow). 32, 249–254.

    CAS  Google Scholar 

  6. Dergunova L.V., Raevskaya N.M., Vladychenskaya I.P., Limborska S.A. 2003. Structural and functional analyses of the Hfb1, Hmob3, and Hmob33 cDNAs as an example of human brain-specific gene studies. Mol. Biol. (Moscow.) 37, 273–280.

    Article  CAS  Google Scholar 

  7. Vladychenskaya I.P., Dergunova L.V., Dmitrieva V.G., Limborska S.A. 2004. Human gene MOB: Structure specification and aspects of transcriptional activity. Gene. 338, 257–265.

    Article  CAS  PubMed  Google Scholar 

  8. Vladychenskaya I.P., Dergunova L.V., Limborska S.A. 2002. In vitro and in silico analysis of the predicted human MOB gene encoding a phylogenetically conserved transmembrane protein. Biomol. Eng. 18, 263–268.

    Article  CAS  PubMed  Google Scholar 

  9. Huitema K., Van Den Dikkenberg J., Brouwers J.F.H.M., Holthuis J.C.M. 2004. Identification of a family of animal sphingomyelin synthases. EMBO J. 23, 33–44.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Yamaoka S., Miyaji M., Kitano T., Umehara H., Okazaki T. 2004. Expression cloning of a human cDNA restoring sphingomyelin synthesis and cell growth in sphingomyelin synthase-defective lymphoid cells. J. Biol. Chem. 279, 18688–18693.

    Article  CAS  PubMed  Google Scholar 

  11. Barceló-Coblijn G., Martin M.L., De Almeida R.F.M., Noguera-Salvà M.A., Marcilla-Etxenike A., Guardiola-Serrano F., Lüth A., Kleuser B., Halver J.E., Escribá P.V. 2011. Sphingomyelin and sphingomyelin synthase (SMS) in the malignant transformation of glioma cells and in 2-hydroxyoleic acid therapy. Proc. Natl. Acad. Sci. U. S. A. 108, 19569–19574.

    Article  PubMed Central  PubMed  Google Scholar 

  12. Shakor A.B.A., Taniguchi M., Kitatani K., Hashimoto M., Asano S., Hayashi A., Nomura K., Bielawski J., Bielawska A., Watanabe K., Kobayashi T., Igarashi Y., Umehara H., Takeya H., Okazaki T. 2011. Sphingomyelin synthase 1-generated sphingomyelin plays an important role in transferrin trafficking and cell proliferation. J. Biol. Chem. 286, 36053–36062.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Subathra M., Qureshi A., Luberto C. 2011. Sphingomyelin synthases regulate protein trafficking and secretion. PLoS ONE. 6, e23644.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Yan N., Ding T., Dong J., Li Y., Wu M. 2011. Sphingomyelin synthase overexpression increases cholesterol accumulation and decreases cholesterol secretion in liver cells. Lipids Health Dis. 10, 46.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Rozhkova A.V., Dmitrieva V.G., Zhapparova O.N., Sudarkina O.Y., Nadezhdina E.S., Limborska S.A., Dergunova L.V. 2011. Human sphingomyelin synthase 1 gene (SMS1): Organization, multiple mRNA splice variants and expression in adult tissues. Gene. 481, 65–75.

    Article  CAS  PubMed  Google Scholar 

  16. Dergunova L., Rozhkova A., Sudarkina O., Limborska S. 2013. The use of alternative polyadenylation in the tissue-specific regulation of human SMS1 gene expression. Mol. Biol. Rep. 40, 6685–6690.

    Article  CAS  PubMed  Google Scholar 

  17. Sambrook J., Fritsch E.F., Maniatis T. 1989. Molecular Cloning: A Laboratory Manual. Cold Spring Harbor, NY: Cold Spring Harbor Lab. Press.

    Google Scholar 

  18. Chomczynski P. 1992. One-hour downward alkaline capillary transfer for blotting of DNA and RNA. Anal. Biochem. 201, 134–139.

    Article  CAS  PubMed  Google Scholar 

  19. Kaminska B., Filipkowski R.K., Zurkowska G., Lason W., Przewlocki R., Kaczmarek L. 1994. Dynamic changes in the composition of the AP-1 transcription factor DNA-binding activity in rat brain following kainateinduced seizures and cell death. Eur. J. Neurosci. 6, 1558–1566.

    Article  CAS  PubMed  Google Scholar 

  20. Pfaffl M.W., Horgan G.W., Dempfle L. 2002. Relative expression software tool (REST.) for group-wise comparison and statistical analysis of relative expression results in real-time PCR. Nucleic Acids Res. 30, e36.

    Article  PubMed Central  PubMed  Google Scholar 

  21. Takai D., Jones P.A. 2002. Comprehensive analysis of CpG islands in human chromosomes 21 and 22. Proc. Natl. Acad. Sci. U. S. A. 99, 3740–3745.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Zuker M. 2003. Mfold web server for nucleic acid folding and hybridization prediction. Nucleic Acids Res. 31, 3406–3415.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Jacox E., Gotea V., Ovcharenko I., Elnitski L. 2010. Tissue-specific and ubiquitous expression patterns from alternative promoters of human genes. PLoS ONE. 5, e12274.

    Article  PubMed Central  PubMed  Google Scholar 

  24. Chen J., Randeva H.S. 2010. Genomic organization and regulation of the human orexin (hypocretin) receptor 2 gene: Identification of alternative promoters. Biochem. J. 427, 377–390.

    Article  CAS  PubMed  Google Scholar 

  25. Longo A., Librizzi M., Naselli F., Caradonna F., Tobiasch E., Luparello C. 2013. PTHrP in differentiating human mesenchymal stem cells: Transcript isoform expression, promoter methylation, and protein accumulation. Biochimie. 95, 1888–1896.

    Article  CAS  PubMed  Google Scholar 

  26. Guske K., Schmitz B., Schelleckes M., Duning K., Kremerskothen J., Pavenstädt H., Brand S.-M., Brand E. 2014. Tissue-specific differences in the regulation of KIBRA gene expression involve transcription factor TCF7L2 and a complex alternative promoter system. J. Mol. Med. (Berlin). 92, 185–196.

    Article  CAS  Google Scholar 

  27. Hoivik E.A., Witsoe S.L., Bergheim I.R., Xu Y., Jakobsson I., Tengholm A., Doskeland S.O., Bakke M. 2013. DNA methylation of alternative promoters directs tissue specific expression of Epac2 isoforms. PLoS ONE. 8, e67925.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Hertel J., Hirche C., Wissmann C., Ebert M., Höcker M. 2014. Transcription of the vascular endothelial growth factor receptor-3 (VEGFR3) gene is regulated by the zinc finger proteins Sp1 and Sp3 and is under epigenetic control. Cell Oncol. (Dordrecht). 37, 131–145.

    Article  CAS  Google Scholar 

  29. Jiang Z., Qian L., Zou H., Jia Y., Ni Y., Yang X., Jiang Z., Zhao R. 2014. Porcine glucocorticoid receptor (NR3C1) gene: Tissue-specificity of transcriptional strength and glucocorticoid responsiveness of alternative promoters. J. Steroid Biochem. Mol. Biol. 141, 87–93.

    Article  CAS  PubMed  Google Scholar 

  30. Kudla G., Murray A.W., Tollervey D., Plotkin J.B. 2009. Coding-sequence determinants of gene expression in Escherichia coli. Science. 324, 255–258.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Davuluri R.V., Suzuki Y., Sugano S., Zhang M.Q. 2000. CART classification of human 5′ UTR sequences. Genome Res. 10, 1807–1816.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Wang L., Wessler S.R. 2001. Role of mRNA Secondary structure in translational repression of the maize transcriptional activator Lc(1,2). Plant Physiol. 125, 1380–1387.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Kozak M. 1991. Structural features in eukaryotic mRNAs that modulate the initiation of translation. J. Biol. Chem. 266, 19867–19870.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Molecular Genetics, Russian Academy of Sciences, Moscow, 123182, Russia

    A. V. Rozhkova, I. B. Filippenkov, O. Yu. Sudarkina, S. A. Limborska & L. V. Dergunova

  2. Research Institute of Cerebrovascular Pathology and Stroke, Pirogov Russian National Research Medical University, Moscow, 117997, Russia

    S. A. Limborska & L. V. Dergunova

Authors
  1. A. V. Rozhkova
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. I. B. Filippenkov
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. O. Yu. Sudarkina
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S. A. Limborska
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. L. V. Dergunova
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to L. V. Dergunova.

Additional information

Original Russian Text © A.V. Rozhkova, I.B. Filippenkov, O.Yu. Sudarkina, S.A. Limborska, L.V. Dergunova, 2015, published in Molekulyarnaya Biologiya, 2015, Vol. 49, No. 2, pp. 325–333.

These authors contributed equally to the study.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rozhkova, A.V., Filippenkov, I.B., Sudarkina, O.Y. et al. Alternative promoters located in SGMS1 gene introns participate in regulation of its expression in human tissues. Mol Biol 49, 287–294 (2015). https://doi.org/10.1134/S002689331501015X

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S002689331501015X

Keywords

Search

Navigation