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DNA origami: a tool to evaluate and harness transcription factors

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Abstract

Alongside other players, such as CpG methylation and the “histone code,” transcription factors (TFs) represent a key feature of gene regulation. TFs are implicated in critical cellular processes, ranging from cell death, growth, and differentiation, up to intranuclear signaling of steroid and other hormones, physical entities, and hypoxia regulation. Notwithstanding an extensive body of research in this field, several questions and therapeutic options remain unanswered and unexplored, respectively. Of note, many of these TFs represent therapeutic targets, which are either difficult to be pharmacologically tackled or are still not drugged via traditional approaches, such as small-molecule inhibition. Upon providing a brief overview of TFs, we focus herein on how synthetic biology/medicine could assist in their study as well as their therapeutic targeting. Specifically, we contend that DNA origami, i.e., a novel synthetic DNA nanotechnological approach, represents an excellent synthetic biology/medicine tool to accomplish the above goals, since it can harness several vital characteristics of DNA: DNA polymerization, DNA complementarity, DNA “programmability,” and DNA “editability.” In doing so, DNA origami can be applied to study TF dynamics during DNA transcription, to elucidate xeno-nucleic acids with distinct scaffolds and unconventional base pairs, and to use TFs as competitors of oncogene-engaged promoters. Overall, because of their potential for high-throughput design and their favorable pharmacodynamic and pharmacokinetic properties, DNA origami can be a novel armory for TF-related drug design. Last, we discuss future trends in the field, such as RNA origami and innovative DNA origami–based therapeutic delivery approaches.

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References

  1. Gomes B, Ashley EA (2023) Artificial intelligence in molecular medicine. N Engl J Med 388:2456–2465

    Article  CAS  PubMed  Google Scholar 

  2. Papavassiliou AG (1995) Molecular medicine. transcription factors. N Engl J Med 332:45–47

    Article  CAS  PubMed  Google Scholar 

  3. Karlebach G, Shamir R (2008) Modelling and analysis of gene regulatory networks. Nat Rev Mol Cell Biol 9:770–780

    Article  CAS  PubMed  Google Scholar 

  4. Robichaux RR, Rodrigue PR (2003) Using origami to promote geometric communication. Mathematics Teaching in the Middle School 9(4):222–229. https://doi.org/10.5951/MTMS.9.4.0222

    Article  Google Scholar 

  5. Shih WM, Quispe JD, Joyce GF (2004) A 1.7-kilobase single-stranded DNA that folds into a nanoscale octahedron. Nature 427:618–621

    Article  CAS  PubMed  Google Scholar 

  6. Yan H, LaBean TH, Feng L, Reif JH (2003) Directed nucleation assembly of DNA tile complexes for barcode-patterned lattices. Proc Natl Acad Sci USA 100:8103–81108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Dey S, Fan C, Gothelf KV, Li J, Lin C, Liu L et al (2021) DNA origami Nat Rev Methods Primers 1:13. https://doi.org/10.1038/s43586-020-00009-8

    Article  CAS  Google Scholar 

  8. Thomsen RP, Malle MG, Okholm AH, Krishnan S, Bohr SS-R, Sørensen RS et al (2019) A large size-selective DNA nanopore with sensing applications. Nat Commun 10:5655

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Chandrasekaran AR, Anderson N, Kizer M, Halvorsen K, Wang X (2016) Beyond the fold: emerging biological applications of DNA origami. ChemBioChem 17:1081–1089

    Article  CAS  PubMed  Google Scholar 

  10. Dai L, Liu P, Hu X, Zhao X, Shao G, Tian Y (2021) DNA origami: an outstanding platform for functions in nanophotonics and cancer therapy. Analyst 146(6):1807–1819. https://doi.org/10.1039/D0AN02160A

    Article  CAS  PubMed  Google Scholar 

  11. Kim M, Lee C, Jeon K, Lee JY, Kim Y-J, Lee JG et al (2023) Harnessing a paper-folding mechanism for reconfigurable DNA origami. Nature 619:78–86

    Article  CAS  PubMed  Google Scholar 

  12. Rothemund PW (2006) Folding DNA to create nanoscale shapes and patterns. Nature 440:297–302

    Article  CAS  PubMed  Google Scholar 

  13. Kaur C, Kaur V, Rai S, Sharma M, Sen T (2023) Selective recognition of the amyloid marker single thioflavin T using DNA origami-based gold nanobipyramid nanoantennas. Nanoscale 15:6170–6178

    Article  CAS  PubMed  Google Scholar 

  14. Raveendran M, Lee AJ, Sharma R, Wälti C, Actis P (2020) Rational design of DNA nanostructures for single molecule biosensing. Nat Commun 11:4384

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Taghdisi SM, Danesh NM, Nameghi MA, Ramezani M, Alibolandi M, Abnous K (2020) A DNA triangular prism-based fluorescent aptasensor for ultrasensitive detection of prostate-specific antigen. Anal Chim Acta 1120:36–42

    Article  CAS  PubMed  Google Scholar 

  16. Willaert RG, Kasas S (2022) High-speed atomic force microscopy visualization of protein-DNA interactions using DNA origami frames. Methods Mol Biol 2516:157–167

    Article  CAS  PubMed  Google Scholar 

  17. Endo M, Sugiyama H (2018) Direct observation of dynamic movement of DNA molecules in DNA origami imaged using high-speed AFM. Methods Mol Biol 1814:213–224

    Article  CAS  PubMed  Google Scholar 

  18. Shah SIH, Lim S (2019) Bioinspired DNA origami quasi-Yagi helical antenna with beam direction and beamwidth switching capability. Sci Rep 9:14312

    Article  PubMed  PubMed Central  Google Scholar 

  19. Zähringer J, Cole F, Bohlen J, Steiner F, Kamińska I, Tinnefeld P (2023) Combining pMINFLUX, graphene energy transfer and DNA-PAINT for nanometer precise 3D super-resolution microscopy. Light Sci Appl 12:70

    Article  PubMed  PubMed Central  Google Scholar 

  20. Funke JJ, Dietz H (2016) Placing molecules with Bohr radius resolution using DNA origami. Nat Nanotechnol 11:47–52

    Article  CAS  PubMed  Google Scholar 

  21. Zhang Y, Ptacin JL, Fischer EC, Aerni HR, Caffaro CE, San Jose K et al (2017) A semi-synthetic organism that stores and retrieves increased genetic information. Nature 551:644–647

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kramm K, Schröder T, Gouge J, Vera AM, Gupta K, Heiss FB et al (2020) DNA origami-based single-molecule force spectroscopy elucidates RNA polymerase III pre-initiation complex stability. Nat Commun 11:2828

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Nguyen M-K, Nguyen VH, Natarajan AK, Huang Y, Ryssy J, Shen B et al (2020) Ultrathin silica coating of DNA origami nanostructures. Chem Mater 32:6657–6665

    Article  CAS  Google Scholar 

  24. Agarwal NP, Matthies M, Gür FN, Osada K, Schmidt TL (2017) Block Copolymer micellization as a protection strategy for DNA origami. Angew Chem Int Ed Engl 56:5460–5464

    Article  CAS  PubMed  Google Scholar 

  25. Ponnuswamy N, Bastings MMC, Nathwani B, Ryu JH, Chou LYT, Vinther M et al (2017) Oligolysine-based coating protects DNA nanostructures from low-salt denaturation and nuclease degradation. Nat Commun 8:15654

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Cogoi S, Paramasivam M, Filichev V, Géci I, Pedersen EB, Xodo LE (2009) Identification of a new G-quadruplex motif in the KRAS promoter and design of pyrene-modified G4-decoys with antiproliferative activity in pancreatic cancer cells. J Med Chem 52:564–568

    Article  CAS  PubMed  Google Scholar 

  27. Rhodes D, Lipps HJ (2015) G-quadruplexes and their regulatory roles in biology. Nucleic Acids Res 43:8627–8637

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Moses JE, Moorhouse AD (2007) The growing applications of click chemistry. Chem Soc Rev 36:1249–1262

    Article  CAS  PubMed  Google Scholar 

  29. Natarajan AK, Ryssy J, Kuzyk A (2023) A DNA origami-based device for investigating DNA bending proteins by transmission electron microscopy. Nanoscale 15:3212–3218

    Article  CAS  PubMed  Google Scholar 

  30. Yamamoto S, De D, Hidaka K, Kim KK, Endo M, Sugiyama H (2014) Single molecule visualization and characterization of Sox2-Pax6 complex formation on a regulatory DNA element using a DNA origami frame. Nano Lett 14:2286–2292

    Article  CAS  PubMed  Google Scholar 

  31. Takusagawa M, Kobayashi Y, Fukao Y, Hidaka K, Endo M, Sugiyama H et al (2021) HBD1 protein with a tandem repeat of two HMG-box domains is a DNA clip to organize chloroplast nucleoids in Chlamydomonas reinhardtii. Proc Natl Acad Sci USA 118:e2021053118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Angelin A, Kassel O, Rastegar S, Strähle U, Niemeyer CM (2016) Protein-functionalized DNA nanostructures as tools to control transcription in zebrafish embryos. ChemistryOpen 6:33–39

    Article  PubMed  PubMed Central  Google Scholar 

  33. Martin TG, Bharat TA, Joerger AC, Bai XC, Praetorius F, Fersht AR, el, (2016) Design of a molecular support for cryo-EM structure determination. Proc Natl Acad Sci USA 113:E7456–E7463

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Funke JJ, Ketterer P, Lieleg C, Korber P, Dietz H (2016) Exploring nucleosome unwrapping using DNA origami. Nano Lett 16:7891–7898

    Article  CAS  PubMed  Google Scholar 

  35. Le JV, Luo Y, Darcy MA, Lucas CR, Goodwin MF, Poirier MG et al (2016) Probing nucleosome stability with a DNA origami nanocaliper. ACS Nano 10:7073–7084

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Nickels PC, Wünsch B, Holzmeister P, Bae W, Kneer LM, Grohmann D et al (2016) Molecular force spectroscopy with a DNA origami-based nanoscopic force clamp. Science 354:305–307

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Funke JJ, Ketterer P, Lieleg C, Schunter S, Korber P, Dietz H (2016) Uncovering the forces between nucleosomes using DNA origami. Sci Adv 2:e1600974

    Article  PubMed  PubMed Central  Google Scholar 

  38. Al-Zarah H, Serag MF, Abadi M, Habuchi S (2023) Self-assembly of geometry-based DNA origami-histone protein hybrid nanostructures for constructing rationally-designed higher-order structures. ACS Appl Nano Mater 6(11):9515–9522. https://doi.org/10.1021/acsanm.3c01185

    Article  CAS  Google Scholar 

  39. Molbay M, Kick B, Zhao S, Todorov MI, Ohn T-L, Roth S et al (2023) Single-cell precision nanotechnology in vivo. bioRxiv 7(24):550304. https://doi.org/10.1101/2023.07.24.550304

  40. Poppleton E, Urbanek N, Chakraborty T, Griffo A, Monari L, Göpfrich K (2023) RNA origami: design, simulation and application. RNA Biol 20:510–524

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Afonin KA, Viard M, Koyfman AY, Martins AN, Kasprzak WK, Panigai M et al (2021) Multifunctional RNA nanoparticles. In: Afonin KA, Chandler M (eds) Therapeutic RNA Nanotechnology, 1st edn. Jenny Stanford Publishing, New York, pp 295–324

    Chapter  Google Scholar 

  42. Han D, Qi X, Myhrvold C, Wang B, Dai M, Jiang S et al (2017) Single-stranded DNA and RNA origami. Science 358:eaao2648

  43. Praetorius F, Kick B, Behler KL, Honemann MN, Weuster-Botz D, Dietz H (2017) Biotechnological mass production of DNA origami. Nature 552:84–87

    Article  CAS  PubMed  Google Scholar 

  44. Harcourt EM, Kietrys AM, Kool ET (2017) Chemical and structural effects of base modifications in messengar RNA. Nature 541:339–346

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Rossi-Gendron C, El Fakih F, Bourdon L, Nakazawa K, Finkel J, Triomphe N et al (2023) Isothermal self-assembly of multicomponent and evolutive DNA nanostructures. Nat Nanotechnol. https://doi.org/10.1038/s41565-023-01468-2. Online ahead of print

  46. Sato K, Akiyama M, Sakakibara Y (2021) RNA secondary structure prediction using deep learning with thermodynamic integration. Nat Commun 12:941

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Sunbul M, Lackner J, Martin A, Englert D, Hacene B, Grün F et al (2021) Super-resolution RNA imaging using a rhodamine-binding aptamer with fast exchange kinetics. Nat Biotechnol 39:686–690

    Article  CAS  PubMed  Google Scholar 

  48. Zenk J, Tuntivate C, Schulman R (2016) Kinetics and thermodynamics of Watson-Crick base pairing driven DNA origami dimerization. J Am Chem Soc 138:3346–3354

    Article  CAS  PubMed  Google Scholar 

  49. Jasinski DL, Li H, Guo P (2018) The effect of size and shape of RNA nanoparticles on biodistribution. Mol Ther 26:784–792

    Article  CAS  PubMed  Google Scholar 

  50. Zhu L, Luo J, Ren K (2023) Nucleic acid-based artificial nanocarriers for gene therapy. J Mater Chem B 11:261–279

    Article  CAS  PubMed  Google Scholar 

  51. Bulcha JT, Wang Y, Ma H, Tai PW, Gao G (2021) Viral vector platforms within the gene therapy landscape. Signal Transduct Ttarget Ther 6:53

    Article  CAS  Google Scholar 

  52. Bastings MMC (2023) Biotechnological frontiers of DNA nanomaterials continue to expand: bacterial infection using virus-inspired capsids. Angew Chem Int Ed Engl 62:e202218334

    Article  CAS  PubMed  Google Scholar 

  53. Schüller VJ, Heidegger S, Sandholzer N, Nickels PC, Suhartha NA, Endres S et al (2011) Cellular immunostimulation by CpG-sequence-coated DNA origami structures. ACS Nano 5:9696–9702

    Article  PubMed  Google Scholar 

  54. Du RR, Cedrone E, Romanov A, Falkovich R, Dobrovolskaia MA, Bathe M (2022) Innate immune stimulation using 3d wireframe dna origami. ACS Nano 16:20340–20352

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Mohri K, Nishikawa M, Takahashi Y, Takakura Y (2014) DNA nanotechnology-based development of delivery systems for bioactive compounds. Eur J Pharm Sci 58:26–33

    Article  CAS  PubMed  Google Scholar 

  56. Wu X, Yang C, Wang H, Lu X, Shang Y, Liu Q et al (2023) Genetically encoded DNA origami for gene therapy in vivo. J Am Chem Soc 145:9343–9353

    Article  CAS  PubMed  Google Scholar 

  57. Balakrishnan D, Wilkens GD, Heddle JG (2019) Delivering DNA origami to cells Nanomedicine (Lond) 14:911–925

    Article  CAS  PubMed  Google Scholar 

  58. Kogikoski S, Ameixa J, Mostafa A, Bald I (2023) Lab-on-a-DNA origami: nanoengineered single-molecule platforms. Chem Commun 59:4726–4741

    Article  CAS  Google Scholar 

  59. Zhang H, Demirer GS, Zhang H, Ye T, Goh NS, Aditham AJ et al (2019) DNA nanostructures coordinate gene silencing in mature plants. Proc Natl Acad Sci USA 116:7543–7548

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Liedl A, Grießing J, Kretzmann JA, Dietz H (2023) Active nuclear import of mammalian cell-expressible DNA origami. J Am Chem Soc 145:4946–4950

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Kretzmann JA, Liedl A, Monferrer A, Mykhailiuk V, Beerkens S, Dietz H (2023) Gene-encoding DNA origami for mammalian cell expression. Nat Commun 14:1017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

A-FAM expresses his thanks to Anna Gkika for continuous moral support during this study, to Aaron B. Hunyady for proofreading the manuscript, and to Hassan Zaman for figure editing.

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This research received no external funding.

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Authors and Affiliations

  1. BGI-Shenzhen, Shenzhen, Guangdong, China

    Alexios-Fotios A. Mentis

  2. First University Department of Respiratory Medicine, Sotiria’ Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece

    Kostas A. Papavassiliou

  3. Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, 11527, Greece

    Athanasios G. Papavassiliou

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  1. Alexios-Fotios A. Mentis
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  2. Kostas A. Papavassiliou
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  3. Athanasios G. Papavassiliou
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Correspondence to Athanasios G. Papavassiliou.

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Mentis, AF.A., Papavassiliou, K.A. & Papavassiliou, A.G. DNA origami: a tool to evaluate and harness transcription factors. J Mol Med 101, 1493–1498 (2023). https://doi.org/10.1007/s00109-023-02380-x

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