Skip to main content

Advertisement

SpringerLink
Log in

Genome-wide analyses reveal the regulatory roles of DNA methylation-regulated alternative promoter transcripts in breast cancer

  • Original Investigation
  • Published:
Human Genetics Aims and scope Submit manuscript

Abstract

A certain proportion of genes are regulated by multiple, distinct promoters, revealing a dynamic landscape of the cancer transcriptome. However, the contribution of alternative promoters (APs) in breast cancer (BRCA) remains largely unexplored. Here, we identified 3654 genes with multiple promoters in BRCA patients, and 53 of them could generate distinct AP transcripts that are dysregulated and prognosis-related in BRCA, namely prognosis-related dysregulated AP (prdeAP) transcripts. Interestingly, when we searched for the genomic signatures of these prdeAP genes, we found that the promoter regions of 92% of the prdeAP genes were enriched with abundant DNA methylation signals. Through further bioinformatic analysis and experimental validation, we showed that AP selections of TANK, UNKL, CCL28, and MAP1LC3A were regulated by DNA methylation upon their corresponding promoter regions. Functionally, by overexpressing AP variants of TANK, we found that TANK|55731 could dramatically suppress MDA-MB-231 cell proliferation and migration. Meanwhile, pan-cancer survival analyses suggested that AP variants of TANK provided more accurate prognostic predictive ability than TANK gene in a variety of tumor types, including BRCA. Together, by uncovering the DNA methylation-regulated AP transcripts with tumor prognostic features, our work revealed a novel layer of regulators in BRCA progression and provided potential targets that served as effective biomarkers for anti-BRCA treatment.

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
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Data availability

The datasets analyzed during the current study are available in the TCGA SpliceSeq database (https://bioinformatics.mdanderson.org/TCGASpliceSeq/), and UCSC Xena database (http://xena.ucsc.edu/).

References

  • Ando M, Saito Y, Xu G, Bui NQ, Medetgul-Ernar K, Pu M, Fisch K, Ren S, Sakai A, Fukusumi T, Liu C, Haft S, Pang J, Mark A, Gaykalova DA, Guo T, Favorov AV, Yegnasubramanian S, Fertig EJ, Ha P, Tamayo P, Yamasoba T, Ideker T, Messer K, Califano JA (2019) Chromatin dysregulation and DNA methylation at transcription start sites associated with transcriptional repression in cancers. Nat Commun 10:2188

    Article  PubMed  PubMed Central  Google Scholar 

  • Augereau P, Patsouris A, Bourbouloux E, Gourmelon C, Abadie Lacourtoisie S, Berton Rigaud D, Soulie P, Frenel JS, Campone M (2017) Hormonoresistance in advanced breast cancer: a new revolution in endocrine therapy. Ther Adv Med Oncol 9:335–346

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cai Q, He B, Zhang P, Zhao Z, Peng X, Zhang Y, Xie H, Wang X (2020) Exploration of predictive and prognostic alternative splicing signatures in lung adenocarcinoma using machine learning methods. J Transl Med 18:463

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carninci P, Kasukawa T, Katayama S, Gough J, Frith MC, Maeda N, Oyama R, Ravasi T, Lenhard B, Wells C, Kodzius R, Shimokawa K, Bajic VB, Brenner SE, Batalov S, Forrest AR, Zavolan M, Davis MJ, Wilming LG, Aidinis V, Allen JE, Ambesi-Impiombato A, Apweiler R, Aturaliya RN, Bailey TL, Bansal M, Baxter L, Beisel KW, Bersano T, Bono H, Chalk AM, Chiu KP, Choudhary V, Christoffels A, Clutterbuck DR, Crowe ML, Dalla E, Dalrymple BP, de Bono B, Della Gatta G, di Bernardo D, Down T, Engstrom P, Fagiolini M, Faulkner G, Fletcher CF, Fukushima T, Furuno M, Futaki S, Gariboldi M, Georgii-Hemming P, Gingeras TR, Gojobori T, Green RE, Gustincich S, Harbers M, Hayashi Y, Hensch TK, Hirokawa N, Hill D, Huminiecki L, Iacono M, Ikeo K, Iwama A, Ishikawa T, Jakt M, Kanapin A, Katoh M, Kawasawa Y, Kelso J, Kitamura H, Kitano H, Kollias G, Krishnan SP, Kruger A, Kummerfeld SK, Kurochkin IV, Lareau LF, Lazarevic D, Lipovich L, Liu J, Liuni S, McWilliam S, Madan Babu M, Madera M, Marchionni L, Matsuda H, Matsuzawa S, Miki H, Mignone F, Miyake S, Morris K, Mottagui-Tabar S, Mulder N, Nakano N, Nakauchi H, Ng P, Nilsson R, Nishiguchi S, Nishikawa S, Nori F, Ohara O, Okazaki Y, Orlando V, Pang KC, Pavan WJ, Pavesi G, Pesole G, Petrovsky N, Piazza S, Reed J, Reid JF, Ring BZ, Ringwald M, Rost B, Ruan Y, Salzberg SL, Sandelin A, Schneider C, Schonbach C, Sekiguchi K, Semple CA, Seno S, Sessa L, Sheng Y, Shibata Y, Shimada H, Shimada K, Silva D, Sinclair B, Sperling S, Stupka E, Sugiura K, Sultana R, Takenaka Y, Taki K, Tammoja K, Tan SL, Tang S, Taylor MS, Tegner J, Teichmann SA, Ueda HR, van Nimwegen E, Verardo R, Wei CL, Yagi K, Yamanishi H, Zabarovsky E, Zhu S, Zimmer A, Hide W, Bult C, Grimmond SM, Teasdale RD, Liu ET, Brusic V, Quackenbush J, Wahlestedt C, Mattick JS, Hume DA, Kai C, Sasaki D, Tomaru Y, Fukuda S, Kanamori-Katayama M, Suzuki M, Aoki J, Arakawa T, Iida J, Imamura K, Itoh M, Kato T, Kawaji H, Kawagashira N, Kawashima T, Kojima M, Kondo S, Konno H, Nakano K, Ninomiya N, Nishio T, Okada M, Plessy C, Shibata K, Shiraki T, Suzuki S, Tagami M, Waki K, Watahiki A, Okamura-Oho Y, Suzuki H, Kawai J, Hayashizaki Y (2005) The transcriptional landscape of the mammalian genome. Science 309:1559–1563

    Article  CAS  PubMed  Google Scholar 

  • Cui Y, Lyu X, Ding L, Ke L, Yang D, Pirouz M, Qi Y, Ong J, Gao G, Du P, Gregory RI (2021) Global miRNA dosage control of embryonic germ layer specification. Nature 593:602–606

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Curigliano G (2012) New drugs for breast cancer subtypes: targeting driver pathways to overcome resistance. Cancer Treat Rev 38:303–310

    Article  CAS  PubMed  Google Scholar 

  • Davies C, Pan H, Godwin J, Gray R, Arriagada R, Raina V, Abraham M, Medeiros Alencar VH, Badran A, Bonfill X, Bradbury J, Clarke M, Collins R, Davis SR, Delmestri A, Forbes JF, Haddad P, Hou MF, Inbar M, Khaled H, Kielanowska J, Kwan WH, Mathew BS, Mittra I, Muller B, Nicolucci A, Peralta O, Pernas F, Petruzelka L, Pienkowski T, Radhika R, Rajan B, Rubach MT, Tort S, Urrutia G, Valentini M, Wang Y, Peto R (2013) Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet 381:805–816

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Davuluri RV, Suzuki Y, Sugano S, Plass C, Huang TH (2008) The functional consequences of alternative promoter use in mammalian genomes. Trends Genet 24:167–177

    Article  CAS  PubMed  Google Scholar 

  • Deaton AM, Bird A (2011) CpG islands and the regulation of transcription. Genes Dev 25:1010–1022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • DeCensi A, Puntoni M, Guerrieri-Gonzaga A, Caviglia S, Avino F, Cortesi L, Taverniti C, Pacquola MG, Falcini F, Gulisano M, Digennaro M, Cariello A, Cagossi K, Pinotti G, Lazzeroni M, Serrano D, Branchi D, Campora S, Petrera M, Buttiron Webber T, Boni L, Bonanni B (2019) Randomized Placebo Controlled Trial of Low-Dose Tamoxifen to Prevent Local and Contralateral Recurrence in Breast Intraepithelial Neoplasia. J Clin Oncol 37:1629–1637

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Demircioglu D, Cukuroglu E, Kindermans M, Nandi T, Calabrese C, Fonseca NA, Kahles A, Lehmann KV, Stegle O, Brazma A, Brooks AN, Ratsch G, Tan P, Goke J (2019) A Pan-cancer Transcriptome Analysis Reveals Pervasive Regulation through Alternative Promoters. Cell 178(1465–77):e17

    Google Scholar 

  • Du JX, Chen C, Luo YH, Cai JL, Cai CZ, Xu J, Ni XJ, Zhu W (2020) Establishment and validation of a novel autophagy-related gene signature for patients with breast cancer. Gene 762:144974

    Article  CAS  PubMed  Google Scholar 

  • Ebrahimi N, Kharazmi K, Ghanaatian M, Miraghel SA, Amiri Y, Seyedebrahimi SS, Mobarak H, Yazdani E, Parkhideh S, Hamblin MR, Aref AR (2022) Role of the Wnt and GTPase pathways in breast cancer tumorigenesis and treatment. Cytokine Growth Factor Rev 67:11–24

    Article  CAS  PubMed  Google Scholar 

  • Hamaya Y, Suzuki A, Suzuki Y, Tsuchihara K, Yamashita R (2023) Classification and characterization of alternative promoters in 26 lung adenocarcinoma cell lines. Jpn J Clin Oncol 53:97–104

    Article  PubMed  Google Scholar 

  • Harbeck N, Gnant M (2017) Breast cancer. Lancet 389:1134–1150

    Article  PubMed  Google Scholar 

  • Heichman KA, Warren JD (2012) DNA methylation biomarkers and their utility for solid cancer diagnostics. Clin Chem Lab Med 50:1707–1721

    Article  CAS  PubMed  Google Scholar 

  • Huang KK, Huang J, Wu JKL, Lee M, Tay ST, Kumar V, Ramnarayanan K, Padmanabhan N, Xu C, Tan ALK, Chan C, Kappei D, Goke J, Tan P (2021) Long-read transcriptome sequencing reveals abundant promoter diversity in distinct molecular subtypes of gastric cancer. Genome Biol 22:44

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huh JY, Reilly SM, Abu-Odeh M, Murphy AN, Mahata SK, Zhang J, Cho Y, Seo JB, Hung CW, Green CR, Metallo CM, Saltiel AR (2020) TANK-Binding Kinase 1 Regulates the Localization of Acyl-CoA Synthetase ACSL1 to Control Hepatic Fatty Acid Oxidation. Cell Metab 32(1012–27):e7

    Google Scholar 

  • Irvine D, Tuerk C, Gold L (1991) SELEXION Systematic Evolution of Ligands by Exponential Enrichment with Integrated Optimization by Non-Linear Analysis. J Mol Biol 222:739–761

    Article  CAS  PubMed  Google Scholar 

  • Jones PA, Baylin SB (2007) The epigenomics of cancer. Cell 128:683–692

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kavallaris M (2010) Microtubules and resistance to tubulin-binding agents. Nat Rev Cancer 10:194–204

    Article  CAS  PubMed  Google Scholar 

  • Kimura K, Wakamatsu A, Suzuki Y, Ota T, Nishikawa T, Yamashita R, Yamamoto J, 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  CAS  PubMed  PubMed Central  Google Scholar 

  • Landry JR, Mager DL, Wilhelm BT (2003) Complex controls: the role of alternative promoters in mammalian genomes. Trends Genet 19:640–648

    Article  CAS  PubMed  Google Scholar 

  • Lev Maor G, Yearim A, Ast G (2015) The alternative role of DNA methylation in splicing regulation. Trends Genet 31:274–280

    Article  CAS  PubMed  Google Scholar 

  • Li S, Guo Y, Hu H, Gao N, Yan X, Zhou Q, Liu H (2023) TANK shapes an immunosuppressive microenvironment and predicts prognosis and therapeutic response in glioma. Front Immunol 14:1138203

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liang Y, Zhang H, Song X, Yang Q (2020) Metastatic heterogeneity of breast cancer: Molecular mechanism and potential therapeutic targets. Semin Cancer Biol 60:14–27

    Article  CAS  PubMed  Google Scholar 

  • Lin KT, Krainer AR (2019) PSI-Sigma: a comprehensive splicing-detection method for short-read and long-read RNA-seq analysis. Bioinformatics 35:5048–5054

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu S, Wang Z, Chen D, Zhang B, Tian RR, Wu J, Zhang Y, Xu K, Yang LM, Cheng C, Ma J, Lv L, Zheng YT, Hu X, Zhang Y, Wang X, Li J (2017) Annotation and cluster analysis of spatiotemporal- and sex-related lncRNA expression in rhesus macaque brain. Genome Res 27:1608–1620

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maunakea AK, Nagarajan RP, Bilenky M, Ballinger TJ, D’Souza C, Fouse SD, Johnson BE, Hong C, Nielsen C, Zhao Y, Turecki G, Delaney A, Varhol R, Thiessen N, Shchors K, Heine VM, Rowitch DH, Xing X, Fiore C, Schillebeeckx M, Jones SJ, Haussler D, Marra MA, Hirst M, Wang T, Costello JF (2010) Conserved role of intragenic DNA methylation in regulating alternative promoters. Nature 466:253–257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mutebi M, Anderson BO, Duggan C, Adebamowo C, Agarwal G, Ali Z, Bird P, Bourque JM, DeBoer R, Gebrim LH, Masetti R, Masood S, Menon M, Nakigudde G, Ng’ang’a A, Niyonzima N, Rositch AF, Unger-Saldana K, Villarreal-Garza C, Dvaladze A, El Saghir NS, Gralow JR, Eniu A (2020) Breast cancer treatment: A phased approach to implementation. Cancer 126(Suppl 10):2365–2378

    Article  PubMed  Google Scholar 

  • Nepal C, Andersen JB (2023) Alternative promoters in CpG depleted regions are prevalently associated with epigenetic misregulation of liver cancer transcriptomes. Nat Commun 14:2712

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nishiyama A, Nakanishi M (2021) Navigating the DNA methylation landscape of cancer. Trends Genet 37:1012–1027

    Article  CAS  PubMed  Google Scholar 

  • Ryan M, Wong WC, Brown R, Akbani R, Su X, Broom B, Melott J, Weinstein J (2016) TCGASpliceSeq a compendium of alternative mRNA splicing in cancer. Nucleic Acids Res 44:D1018–D1022

    Article  CAS  PubMed  Google Scholar 

  • Sarda S, Das A, Vinson C, Hannenhalli S (2017) Distal CpG islands can serve as alternative promoters to transcribe genes with silenced proximal promoters. Genome Res 27:553–566

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schober P, Boer C, Schwarte LA (2018) Correlation Coefficients: Appropriate Use and Interpretation. Anesth Analg 126:1763–1768

    Article  PubMed  Google Scholar 

  • Schubeler D (2015) Function and information content of DNA methylation. Nature 517:321–326

    Article  CAS  PubMed  Google Scholar 

  • Shen T, Xia W, Min S, Yang Z, Cheng L, Wang W, Zhan Q, Shao F, Zhang X, Wang Z, Zhang Y, Shen G, Zhang H, Wu LL, Yu GY, Kong QP, Wang X (2021) A pair of long intergenic non-coding RNA LINC00887 variants act antagonistically to control Carbonic Anhydrase IX transcription upon hypoxia in tongue squamous carcinoma progression. BMC Biol 19:192

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Siegmund D, Wagner J, Wajant H (2022) TNF Receptor Associated Factor 2 (TRAF2) Signaling in Cancer. Cancers (Basel) 14:4055

    Article  CAS  PubMed  Google Scholar 

  • Sun T, Gao Y, Tan W, Ma S, Shi Y, Yao J, Guo Y, Yang M, Zhang X, Zhang Q, Zeng C, Lin D (2007) A six-nucleotide insertion-deletion polymorphism in the CASP8 promoter is associated with susceptibility to multiple cancers. Nat Genet 39:605–613

    Article  CAS  PubMed  Google Scholar 

  • Sun X, Tian Y, Wang J, Sun Z, Zhu Y (2020) Genome-wide analysis reveals the association between alternative splicing and DNA methylation across human solid tumors. BMC Med Genomics 13:4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ushijima T, Hanada K, Gotoh E, Yamori W, Kodama Y, Tanaka H, Kusano M, Fukushima A, Tokizawa M, Yamamoto YY, Tada Y, Suzuki Y, Matsushita T (2017) Light Controls Protein Localization through Phytochrome-Mediated Alternative Promoter Selection. Cell 171(1316–25):e12

    Google Scholar 

  • Yu G, Wang LG, Han Y, He QY (2012) clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS 16:284–287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang S, Wang Y, Gu Y, Zhu J, Ci C, Guo Z, Chen C, Wei Y, Lv W, Liu H, Zhang D, Zhang Y (2018) Specific breast cancer prognosis-subtype distinctions based on DNA methylation patterns. Mol Oncol 12:1047–1060

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank Dr. Xiaoling Liang from the First Affiliated Hospital, Division of Life Sciences and Medicine, University of Science and Technology of China for her constructive suggestions. The authors also thank Core Facility Center for Life Sciences, USTC for their technical support to this project.

Funding

This work was supported by National Natural Science Foundation of China (32170557, and 31970598 to X.W. and 32300450 to T.S.), University Natural Science Research Project of Anhui Province (2022AH050211 to T.S.), and the 2023 Wuhu Science and Technology Plan Project (2023jc14 to T.S.).

Author information

Author notes

  1. Yingdong Song and Tao Shen have contributed equally to this work.

Authors and Affiliations

  1. Department of Geriatrics, Gerontology Institute of Anhui Province, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China

    Yingdong Song, Huihui Sun & Xiangting Wang

  2. Anhui Provincial Key Laboratory of Molecular Enzymology and Mechanism of Major Metabolic Diseases, Anhui Provincial Engineering Research Centre for Molecular Detection and Diagnostics, College of Life Sciences, Anhui Normal University, Wuhu, China

    Tao Shen

  3. Anhui Province Key Laboratory of Geriatric Immunology and Nutrition Therapy, Hefei, China

    Xiangting Wang

Authors
  1. Yingdong Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tao Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Huihui Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiangting Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the study conception and design. The project was supervised and organized by X.W. and T.S. Material preparation, data collection, and analysis were performed by Y.S. and T.S. The first draft of the manuscript was written by X.W., T.S., and Y.S. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Tao Shen or Xiangting Wang.

Ethics declarations

Conflict of interest

The authors have no relevant financial or non-financial interests to disclose.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 2364 KB)

Supplementary file2 (XLSX 120 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Song, Y., Shen, T., Sun, H. et al. Genome-wide analyses reveal the regulatory roles of DNA methylation-regulated alternative promoter transcripts in breast cancer. Hum. Genet. 143, 385–399 (2024). https://doi.org/10.1007/s00439-024-02653-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-024-02653-6

Search

Navigation