Skip to main content

Advertisement

SpringerLink
Log in

A Comprehensive Review on the Role of ZSCAN4 in Embryonic Development, Stem Cells, and Cancer

  • Published:
Stem Cell Reviews and Reports Aims and scope Submit manuscript

Abstract

ZSCAN4 is a transcription factor that plays a pivotal role during early embryonic development. It is a unique gene expressed specifically during the first tide of de novo transcription during the zygotic genome activation. Moreover, it is reported to regulate telomere length in embryonic stem cells and induced pluripotent stem cells. Interestingly, ZSCAN4 is expressed in approximately 5% of the embryonic stem cells in culture at any given time, which points to the fact that it has a tight regulatory system. Furthermore, ZSCAN4, if included in the reprogramming cocktail along with core reprogramming factors, increases the reprogramming efficiency and results in better quality, genetically stable induced pluripotent stem cells. Also, it is reported to have a role in promoting cancer stem cell phenotype and can prospectively be used as a marker for the same. In this review, the multifaceted role of ZSCAN4 in embryonic development, embryonic stem cells, induced pluripotent stem cells, cancer, and germ cells are discussed comprehensively.

Graphical Abstract

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
Fig. 8
Fig. 9

We’re sorry, something doesn't seem to be working properly.

Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.

Data Availability

Not applicable

Code Availability

Not Applicable

References

  1. Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., & Yamanaka, S. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell, 131(5), 861–872. https://doi.org/10.1016/J.CELL.2007.11.019

    Article  CAS  PubMed  Google Scholar 

  2. Yu, J., Vodyanik, M. A., Smuga-Otto, K., Antosiewicz-Bourget, J., Frane, J. L., Tian, S., …, & Thomson, J. A. (2007). Induced pluripotent stem cell lines derived from human somatic cells. Science, 318(5858), 1917–1920. https://doi.org/10.1126/SCIENCE.1151526

  3. Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 126(4), 663–676. https://doi.org/10.1016/J.CELL.2006.07.024

    Article  CAS  PubMed  Google Scholar 

  4. Dey, C., Raina, K., Thool, M., Adhikari, P., Haridhasapavalan, K. K., Sundaravadivelu, P. K., …, & Thummer, R. P. (2022). Auxiliary pluripotency-associated genes and their contributions in the generation of induced pluripotent stem cells. Molecular Players in iPSC Technology, 29–94. https://doi.org/10.1016/B978-0-323-90059-1.00007-5

  5. Falco, G., Lee, S. L., Stanghellini, I., Bassey, U. C., Hamatani, T., & Ko, M. S. H. (2007). Zscan4: A novel gene expressed exclusively in late 2-cell embryos and embryonic stem cells. Developmental Biology, 307(2), 539–550. https://doi.org/10.1016/J.YDBIO.2007.05.003

    Article  CAS  PubMed  Google Scholar 

  6. Zalzman, M., Falco, G., Sharova, L. v., Nishiyama, A., Thomas, M., Lee, S. L., …, & Ko, M. S. H. (2010). Zscan4 regulates telomere elongation and genomic stability in ES cells. Nature, 464(7290), 858–863. https://doi.org/10.1038/NATURE08882

  7. Wang, F., Yin, Y., Ye, X., Liu, K., Zhu, H., Wang, L., …, & Liu, L. (2012). Molecular insights into the heterogeneity of telomere reprogramming in induced pluripotent stem cells. Cell Research, 22(4), 757–768. https://doi.org/10.1038/CR.2011.201

  8. Jiang, J., Lv, W., Ye, X., Wang, L., Zhang, M., Yang, H., …, & Li, J. (2013). Zscan4 promotes genomic stability during reprogramming and dramatically improves the quality of iPS cells as demonstrated by tetraploid complementation. Cell Research, 23(1), 92–106. https://doi.org/10.1038/CR.2012.157

  9. Hirata, T., Amano, T., Nakatake, Y., Amano, M., Piao, Y., Hoang, H. G., & Ko, M. S. H. (2012). Zscan4 transiently reactivates early embryonic genes during the generation of induced pluripotent stem cells. Scientific Reports, 2(1), 1–11. https://doi.org/10.1038/srep00208

    Article  CAS  Google Scholar 

  10. Portney, B. A., Arad, M., Gupta, A., Brown, R. A., Khatri, R., Lin, P. N., …, & Zalzman, M. (2020). ZSCAN4 facilitates chromatin remodeling and promotes the cancer stem cell phenotype. Oncogene, 39(26), 4970–4982. https://doi.org/10.1038/s41388-020-1333-1

  11. Edelstein, L. C., & Collins, T. (2005). The SCAN domain family of zinc finger transcription factors. Gene, 359(1–2), 1–17. https://doi.org/10.1016/J.GENE.2005.06.022

    Article  CAS  PubMed  Google Scholar 

  12. Apweiler, R., Attwood, T. K., Bairoch, A., Bateman, A., Birney, E., Biswas, M., …, & Zdobnov, E. M. (2001). The InterPro database, an integrated documentation resource for protein families, domains and functional sites. Nucleic Acids Research, 29(1), 37–40. https://doi.org/10.1093/NAR/29.1.37

  13. Blum, M., Chang, H. Y., Chuguransky, S., Grego, T., Kandasaamy, S., Mitchell, A., …, & Finn, R. D. (2021). The InterPro protein families and domains database: 20 years on. Nucleic Acids Research, 49(D1), D344–D354. https://doi.org/10.1093/NAR/GKAA977

  14. Williams, A. J., Khachigian, L. M., Shows, T., & Collins, T. (1995). Isolation and Characterization of a novel zinc-finger protein with transcriptional repressor activity. Journal of Biological Chemistry, 270(38), 22143–22152. https://doi.org/10.1074/JBC.270.38.22143

    Article  CAS  PubMed  Google Scholar 

  15. Pengue, G., Calabró, V., Bartoli, P. C., Pagliuca, A., & Lania, L. (1994). Repression of transcriptional activity at a distance by the evolutionarily conserved KRAB domain present in a subfamily of zinc finger proteins. Nucleic acids research, 22(15), 2908–2914. https://doi.org/10.1093/NAR/22.15.2908

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Storm, M. P., Kumpfmueller, B., Thompson, B., Kolde, R., Vilo, J., Hummel, O., …, & Welham, M. J. (2009). Characterization of the phosphoinositide 3-kinase-dependent transcriptome in murine embryonic stem cells: Identification of novel regulators of pluripotency. Stem Cells, 27(4), 764–775. https://doi.org/10.1002/stem.3

  17. Dan, J., Rousseau, P., Hardikar, S., Veland, N., Wong, J., Autexier, C., & Chen, T. (2017). Zscan4 inhibits maintenance DNA methylation to facilitate telomere elongation in mouse embryonic stem cells. Cell Reports, 20(8), 1936–1949. https://doi.org/10.1016/J.CELREP.2017.07.070

    Article  CAS  PubMed  Google Scholar 

  18. Pavletich, N. P., & Pabo, C. O. (1991). Zinc finger-DNA recognition: Crystal structure of a Zif268-DNA complex at 2.1 A. Science, 252(5007), 809–817. https://doi.org/10.1126/SCIENCE.2028256

    Article  CAS  PubMed  Google Scholar 

  19. Kumpfmueller, B. (2011). Control of embryonic stem cell fate: the role of phosphoinositide 3-kinase signalling and Zscan4, (Doctoral dissertation, University of Bath).

  20. Urnov, F. D., Rebar, E. J., Holmes, M. C., Zhang, H. S., & Gregory, P. D. (2010). Genome editing with engineered zinc finger nucleases. Nature Reviews Genetics, 11(9), 636–646. https://doi.org/10.1038/nrg2842

    Article  CAS  PubMed  Google Scholar 

  21. Perez, E. E., Wang, J., Miller, J. C., Jouvenot, Y., Kim, K. A., Liu, O., …, & June, C. H. (2008). Establishment of HIV-1 resistance in CD4+ T cells by genome editing using zinc-finger nucleases. Nature Biotechnology, 26(7), 808. https://doi.org/10.1038/NBT1410

  22. Garnier, J., Gibrat, J. F., & Robson, B. (1996). GOR method for predicting protein secondary structure from amino acid sequence. Methods in enzymology, 266, 540–553. https://doi.org/10.1016/S0076-6879(96)66034-0

    Article  CAS  PubMed  Google Scholar 

  23. Geourjon, C., & Deléage, G. (1995). SOPMA: Significant improvements in protein secondary structure prediction by consensus prediction from multiple alignments. Bioinformatics, 11(6), 681–684. https://doi.org/10.1093/BIOINFORMATICS/11.6.681

    Article  CAS  Google Scholar 

  24. Jones, D. T. (1999). Protein secondary structure prediction based on position-specific scoring matrices. Journal of molecular biology, 292(2), 195–202. https://doi.org/10.1006/JMBI.1999.3091

    Article  CAS  PubMed  Google Scholar 

  25. Buchan, D. W. A., & Jones, D. T. (2019). The PSIPRED protein analysis workbench: 20 years on. Nucleic Acids Research, 47(W1), W402–W407. https://doi.org/10.1093/NAR/GKZ297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., …, & Hassabis, D. (2021). Highly accurate protein structure prediction with AlphaFold. Nature, 596(7873), 583–589. https://doi.org/10.1038/s41586-021-03819-2

  27. Varadi, M., Anyango, S., Deshpande, M., Nair, S., Natassia, C., Yordanova, G., …, & Velankar, S. (2022). alphafold protein structure database: Massively expanding the structural coverage of protein-sequence space with high-accuracy models. Nucleic Acids Research, 50(D1), D439–D444. https://doi.org/10.1093/NAR/GKAB1061

  28. Garza, A. S., Ahmad, N., & Kumar, R. (2008). Role of intrinsically disordered protein regions/domains in transcriptional regulation. Life sciences, 84(7–8), 189–193. https://doi.org/10.1016/j.lfs.2008.12.002

    Article  CAS  PubMed  Google Scholar 

  29. Smith, L. J., Fiebig, K. M., Schwalbe, H., & Dobson, C. M. (1996). The concept of a random coil: Residual structure in peptides and denatured proteins. Folding and Design, 1(5), R95–R106. https://doi.org/10.1016/S1359-0278(96)00046-6

    Article  CAS  PubMed  Google Scholar 

  30. Papadopoulos, J. S., & Agarwala, R. (2007). COBALT: Constraint-based alignment tool for multiple protein sequences. Bioinformatics, 23(9), 1073–1079. https://doi.org/10.1093/BIOINFORMATICS/BTM076

    Article  CAS  PubMed  Google Scholar 

  31. Crooks, G. E., Hon, G., Chandonia, J. M., & Brenner, S. E. (2004). WebLogo: A sequence logo generator. Genome research, 14(6), 1188–1190. https://doi.org/10.1101/GR.849004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Schneider, T. D., & Stephens, R. M. (1990). Sequence logos: A new way to display consensus sequences. Nucleic Acids Research, 18(20), 6097. https://doi.org/10.1093/NAR/18.20.6097

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kumar, S., Stecher, G., Li, M., Knyaz, C., & Tamura, K. (2018). MEGA X: Molecular evolutionary genetics analysis across computing platforms. Molecular Biology and Evolution, 35(6), 1547–1549. https://doi.org/10.1093/MOLBEV/MSY096

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Storm, M. P., Kumpfmueller, B., Bone, H. K., Buchholz, M., Sanchez Ripoll, Y., Chaudhuri, J. B., …, & Welham, M. J. (2014). Zscan4 is regulated by PI3-kinase and DNA-damaging agents and directly interacts with the transcriptional repressors LSD1 and CtBP2 in mouse embryonic stem cells. PLoS One, 9(3). https://doi.org/10.1371/journal.pone.0089821

  35. Portney, B. A., Khatri, R., Meltzer, W. A., Mariano, J. M., & Zalzman, M. (2018). ZSCAN4 is negatively regulated by the ubiquitin-proteasome system and the E3 ubiquitin ligase RNF20. Biochemical and biophysical research communications, 498(1), 72. https://doi.org/10.1016/J.BBRC.2018.02.155

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Szklarczyk, D., Gable, A. L., Lyon, D., Junge, A., Wyder, S., Huerta-Cepas, J., …, & von Mering, C. (2019). STRING v11: protein–protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Research, 47(D1), D607–D613. https://doi.org/10.1093/NAR/GKY1131

  37. Hendrickson, P. G., Doráis, J. A., Grow, E. J., Whiddon, J. L., Lim, J. W., Wike, C. L., …, & Cairns, B. R. (2017). Conserved roles of mouse DUX and human DUX4 in activating cleavage-stage genes and MERVL/HERVL retrotransposons. Nature Genetics, 49(6), 925–934. https://doi.org/10.1038/ng.3844

  38. Oliva, J., Galasinski, S., Richey, A., Campbell, A. E., Meyers, M. J., Modi, N., …, & Sverdrup, F. M. (2019). Clinically advanced p38 inhibitors suppress DUX4 expression in cellular and animal models of facioscapulohumeral muscular dystrophy. The Journal of Pharmacology and Experimental Therapeutics, 370(2), 219–230. https://doi.org/10.1124/JPET.119.259663

  39. Ferreboeuf, M., Mariot, V., Bessières, B., Vasiljevic, A., Attié-Bitach, T., Collardeau, S., …, & Dumonceaux, J. (2014). DUX4 and DUX4 downstream target genes are expressed in fetal FSHD muscles. Human Molecular Genetics, 23(1), 171–181. https://doi.org/10.1093/HMG/DDT409

  40. Akiyama, T., Xin, L., Oda, M., Sharov, A. A., Amano, M., Piao, Y., …, & Ko, M. S. H. (2015). Transient bursts of Zscan4 expression are accompanied by the rapid derepression of heterochromatin in mouse embryonic stem cells. DNA Research, 22(5), 307–318. https://doi.org/10.1093/DNARES/DSV013

  41. Lee, K., & Gollahon, L. S. (2014). Zscan4 interacts directly with human Rap1 in cancer cells regardless of telomerase status. Cancer Biology & Therapy, 15(8), 1094–1105. https://doi.org/10.4161/CBT.29220

    Article  CAS  Google Scholar 

  42. Lee, K., & Gollahon, L. S. (2015). ZSCAN4 and TRF1: A functionally indirect interaction in cancer cells independent of telomerase activity. Biochemical and Biophysical Research Communications, 466(4), 644–649. https://doi.org/10.1016/J.BBRC.2015.09.107

    Article  CAS  PubMed  Google Scholar 

  43. Zhang, W., Walker, E., Tamplin, O. J., Rossant, J., Stanford, W. L., & Hughes, T. R. (2006). Zfp206 regulates ES cell gene expression and differentiation. Nucleic Acids Research, 34(17), 4780–4790. https://doi.org/10.1093/NAR/GKL631

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Vassena, R., Boué, S., González-Roca, E., Aran, B., Auer, H., Veiga, A., & Belmonte, J. C. I. (2011). Waves of early transcriptional activation and pluripotency program initiation during human preimplantation development. Development, 138(17), 3699–3709. https://doi.org/10.1242/DEV.064741

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Ko, S. B. H., Azuma, S., Yokoyama, Y., Yamamoto, A., Kyokane, K., Niida, S., …, & Ko, M. S. H. (2013). Inflammation increases cells expressing ZSCAN4 and progenitor cell markers in the adult pancreas. American Journal of Physiology - Gastrointestinal and Liver Physiology, 304(12), G1103. https://doi.org/10.1152/AJPGI.00299.2012

  46. Hamatani, T., Carter, M. G., Sharov, A. A., & Ko, M. S. H. (2004). Dynamics of global gene expression changes during mouse preimplantation development. Developmental Cell, 6(1), 117–131. https://doi.org/10.1016/S1534-5807(03)00373-3

    Article  CAS  PubMed  Google Scholar 

  47. Wang, Q., & Latham, K. E. (1997). Requirement for protein synthesis during embryonic genome activation in mice. Molecular Reproduction and Development: Incorporating Gamete Research, 47(3), 265–270. https://doi.org/10.1002/(SICI)1098-2795(199707)47:3%3c265::AID-MRD5%3e3.0.CO;2-J

    Article  CAS  Google Scholar 

  48. Ko, M. S. H., Kitchen, J. R., Wang, X., Threat, T. A., Wang, X., Hasegawa, A., …, & Doi, H. (2000). Large-scale cDNA analysis reveals phased gene expression patterns during preimplantation mouse development. Development, 127(8), 1737–1749. https://doi.org/10.1242/DEV.127.8.1737

  49. Srinivasan, R., Nady, N., Arora, N., Hsieh, L. J., Swigut, T., Narlikar, G. J., …, & Wysocka, J. (2020). Zscan4 binds nucleosomal microsatellite DNA and protects mouse two-cell embryos from DNA damage. Science Advances, 6(12). https://doi.org/10.1126/SCIADV.AAZ9115

  50. Ishiguro, K. ichiro, Monti, M., Akiyama, T., Kimura, H., Chikazawa-Nohtomi, N., Sakota, M., …, & Ko, M. S. H. (2017). Zscan4 is expressed specifically during late meiotic prophase in both spermatogenesis and oogenesis. In Vitro Cellular and Developmental Biology - Animal, 53(2), 167–178. https://doi.org/10.1007/s11626-016-0096-z

  51. Carter, M. G., Stagg, C. A., Falco, G., Yoshikawa, T., Bassey, U. C., Aiba, K., …, & Ko, M. S. H. (2008). An in situ hybridization-based screen for heterogeneously expressed genes in mouse ES cells. Gene Expression Patterns, 8(3), 181–198. https://doi.org/10.1016/J.GEP.2007.10.009

  52. Ishiguro, K. ichiro, Nakatake, Y., Chikazawa-Nohtomi, N., Kimura, H., Akiyama, T., Oda, M., …, & Ko, M. S. H. (2017). Expression analysis of the endogenous Zscan4 locus and its coding proteins in mouse ES cells and preimplantation embryos. In Vitro Cellular & Developmental Biology. Animal, 53(2), 179. https://doi.org/10.1007/S11626-016-0097-Y

  53. Ko, M. S. H. (2016). Zygotic genome activation revisited: Looking through the expression and function of Zscan4. Current topics in Developmental Biology, 120, 103–124. https://doi.org/10.1016/BS.CTDB.2016.04.004

    Article  CAS  PubMed  Google Scholar 

  54. Zeng, F., Baldwin, D. A., & Schultz, R. M. (2004). Transcript profiling during preimplantation mouse development. Developmental Biology, 272(2), 483–496. https://doi.org/10.1016/j.ydbio.2004.05.018

    Article  CAS  PubMed  Google Scholar 

  55. Wang, Q. T., Piotrowska, K., Ciemerych, M. A., Milenkovic, L., Scott, M. P., Davis, R. W., & Zernicka-Goetz, M. (2004). A genome-wide study of gene activity reveals developmental signaling pathways in the preimplantation mouse embryo. Developmental Cell, 6(1), 133–144. https://doi.org/10.1016/S1534-5807(03)00404-0

    Article  CAS  PubMed  Google Scholar 

  56. Hung, S. S. C., Wong, R. C. B., Sharov, A. A., Nakatake, Y., Yu, H., & Ko, M. S. H. (2013). Repression of global protein synthesis by Eif1a-like genes that are expressed specifically in the two-cell embryos and the transient Zscan4-positive state of embryonic stem cells. DNA Research, 20(4), 391–401. https://doi.org/10.1093/DNARES/DST018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Macfarlan, T. S., Gifford, W. D., Driscoll, S., Lettieri, K., Rowe, H. M., Bonanomi, D., …, & Pfaff, S. L. (2012). Embryonic stem cell potency fluctuates with endogenous retrovirus activity. Nature, 487(7405), 57–63. https://doi.org/10.1038/NATURE11244

  58. Eckersley-Maslin, M. A., Svensson, V., Krueger, C., Stubbs, T. M., Giehr, P., Krueger, F., …, & Reik, W. (2016). MERVL/Zscan4 network activation results in transient genome-wide DNA demethylation of mESCs. Cell Reports, 17(1), 179–192. https://doi.org/10.1016/J.CELREP.2016.08.087

  59. Ishiuchi, T., Enriquez-Gasca, R., Mizutani, E., Boškoviä, A., Ziegler-Birling, C., Rodriguez-Terrones, D., …, & Torres-Padilla, M. E. (2015). Early embryonic-like cells are induced by downregulating replication-dependent chromatin assembly. Nature Structural & Molecular Biology, 22(9), 662–671. https://doi.org/10.1038/NSMB.3066

  60. Niwa, H. (2007). How is pluripotency determined and maintained? Development, 134(4), 635–646. https://doi.org/10.1242/DEV.02787

    Article  CAS  PubMed  Google Scholar 

  61. Bone, H. K., Damiano, T., Bartlett, S., Perry, A., Letchford, J., Ripoll, Y. S., …, & Welham, M. J. (2009). Involvement of GSK-3 in regulation of murine embryonic stem cell self-renewal revealed by a series of bisindolylmaleimides. Chemistry & Biology, 16(1), 15–27. https://doi.org/10.1016/J.CHEMBIOL.2008.11.003

  62. Paling, N. R. D., Wheadon, H., Bone, H. K., & Welham, M. J. (2004). Regulation of embryonic stem cell self-renewal by phosphoinositide 3-Kinase-dependent signaling. Journal of Biological Chemistry, 279(46), 48063–48070. https://doi.org/10.1074/JBC.M406467200

    Article  CAS  PubMed  Google Scholar 

  63. Chen, L., & Khillan, J. S. (2008). Promotion of feeder-independent self-renewal of embryonic stem cells by retinol (vitamin A). Stem cells, 26(7), 1858–1864. https://doi.org/10.1634/STEMCELLS.2008-0050

    Article  CAS  PubMed  Google Scholar 

  64. Chen, L., & Khillan, J. S. (2010). A novel signaling by vitamin A/Retinol promotes self renewal of mouse embryonic stem cells by activating PI3K/Akt signaling pathway via insulin-like growth factor-1 receptor. Stem Cells, 28(1), 57–63. https://doi.org/10.1002/STEM.251

    Article  CAS  PubMed  Google Scholar 

  65. Sharova, L. v., Sharov, A. A., Piao, Y., Stagg, C. A., Amano, T., Qian, Y., …, & Ko, M. S. H. (2016). Emergence of undifferentiated colonies from mouse embryonic stem cells undergoing differentiation by retinoic acid treatment. In Vitro Cellular & Developmental Biology. Animal, 52(5), 616–624. https://doi.org/10.1007/S11626-016-0013-5

  66. Amano, T., Hirata, T., Falco, G., Monti, M., Sharova, L. v., Amano, M., …, & Ko, M. S. H. (2013). Zscan4 restores the developmental potency of embryonic stem cells. Nature Communications, 4(1), 1–10. https://doi.org/10.1038/ncomms2966

  67. Dan, J., Liu, Y., Liu, N., Chiourea, M., Okuka, M., Wu, T., …, & Liu, L. (2014). Rif1 maintains telomere length homeostasis of ESCs by mediating heterochromatin silencing. Developmental Cell, 29(1), 7. https://doi.org/10.1016/J.DEVCEL.2014.03.004

  68. Blasco, M. A. (2005). Telomeres and human disease: Ageing, cancer and beyond. Nature Reviews. Genetics, 6(8), 611–622. https://doi.org/10.1038/NRG1656

    Article  CAS  PubMed  Google Scholar 

  69. Bryan, T. M., Englezou, A., Gupta, J., Bacchetti, S., & Reddel, R. R. Telomere elongation in immortal human cells without detectable telomerase activity. The EMBO Journal, 14(17), 4240–4248. https://doi.org/10.1002/j.1460-2075.1995.tb00098.x

  70. Bryan, T. M., Englezou, A., Dalla-Pozza, L., Dunham, M. A., & Reddel, R. R. (1997). Evidence for an alternative mechanism for maintaining telomere length in human tumors and tumor-derived cell lines. Nature Medicine, 3(11), 1271–1274. https://doi.org/10.1038/nm1197-1271

    Article  CAS  PubMed  Google Scholar 

  71. Le, R., Huang, Y., Zhang, Y., Wang, H., Lin, J., Dong, Y., …, & Gao, S. (2021). Dcaf11 activates Zscan4-mediated alternative telomere lengthening in early embryos and embryonic stem cells. Cell Stem Cell, 28(4), 732-747.e9. https://doi.org/10.1016/J.STEM.2020.11.018

  72. Keeney, S., Giroux, C. N., & Kleckner, N. (1997). Meiosis-specific DNA double-strand breaks are catalyzed by Spo11, a member of a widely conserved protein family. Cell, 88(3), 375–384. https://doi.org/10.1016/S0092-8674(00)81876-0

    Article  CAS  PubMed  Google Scholar 

  73. ] Mahadevaiah, S. K., Turner, J. M. A., Baudat, F., Rogakou, E. P., de Boer, P., Blanco-Rodríguez, J., …, & Burgoyne, P. S. (2001). Recombinational DNA double-strand breaks in mice precede synapsis. Nature Genetics, 27(3), 271–276. https://doi.org/10.1038/85830

  74. Reinholdt, L. G., & Schimenti, J. C. (2005). Mei1 is epistatic to Dmc1 during mouse meiosis. Chromosoma, 114(2), 127–134. https://doi.org/10.1007/S00412-005-0346-4

    Article  CAS  PubMed  Google Scholar 

  75. Yin, Y., Liu, N., Ye, X., Guo, R., Hao, J., Wang, F., & Liu, L. (2014). Telomere elongation in parthenogenetic stem cells. Protein and Cell, 5(1), 8–11. https://doi.org/10.1007/s13238-013-0006-z

    Article  PubMed  PubMed Central  Google Scholar 

  76. Guo, R., Ye, X., Yang, J., Zhou, Z., Tian, C., Wang, H., …, & Liu, L. (2018). Feeders facilitate telomere maintenance and chromosomal stability of embryonic stem cells. Nature Communications, 9(1), 1–16. https://doi.org/10.1038/s41467-018-05038-2

  77. Wang, J., Scully, K., Zhu, X., Cai, L., Zhang, J., Prefontaine, G. G., …, & Rosenfeld, M. G. (2007). Opposing LSD1 complexes function in developmental gene activation and repression programmes. Nature, 446(7138), 882–887. https://doi.org/10.1038/NATURE05671

  78. Yu, H. B., Kunarso, G., Hong, F. H., & Stanton, L. W. (2009). Zfp206, Oct4, and Sox2 are integrated components of a transcriptional regulatory network in embryonic stem cells. Journal of Biological Chemistry, 284(45), 31327–31335. https://doi.org/10.1074/JBC.M109.016162/ATTACHMENT/0359F817-6DA3-4C81-B46A-A3AE2ED277C2/MMC1.ZIP

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Tagliaferri, D., de Angelis, M. T., Russo, N. A., Marotta, M., Ceccarelli, M., del Vecchio, L., …, & Falco, G. (2016). Retinoic Acid Specifically Enhances Embryonic Stem Cell Metastate Marked by Zscan4. PLoS One, 11(2), e0147683. https://doi.org/10.1371/JOURNAL.PONE.0147683

  80. Balasubramanian, P., Zhao, L. J., & Chinnadurai, G. (2003). Nicotinamide adenine dinucleotide stimulates oligomerization, interaction with adenovirus E1A and an intrinsic dehydrogenase activity of CtBP. FEBS Letters, 537(1–3), 157–160. https://doi.org/10.1016/S0014-5793(03)00119-4

    Article  CAS  PubMed  Google Scholar 

  81. Dan, J., Li, M., Yang, J., Li, J., Okuka, M., Ye, X., & Liu, L. (2013). Roles for Tbx3 in regulation of two-cell state and telomere elongation in mouse ES cells. Scientific Reports, 3(1), 1–9. https://doi.org/10.1038/srep03492

    Article  Google Scholar 

  82. Paduano, V., Tagliaferri, D., Falco, G., & Ceccarelli, M. (2013). Automated identification and location analysis of marked stem cells colonies in optical microscopy images. PLoS One, 8(12), e80776. https://doi.org/10.1371/JOURNAL.PONE.0080776

    Article  PubMed  PubMed Central  Google Scholar 

  83. de Lange, T. (2009). How telomeres solve the end-protection problem. Science, 326(5955), 948–952. https://doi.org/10.1126/SCIENCE.1170633

    Article  PubMed  PubMed Central  Google Scholar 

  84. Nandakumar, J., & Cech, T. R. (2013). Finding the end: Recruitment of telomerase to telomeres. Nature Reviews. Molecular Cell Biology, 14(2), 69–82. https://doi.org/10.1038/NRM3505

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Hiyama, E., & Hiyama, K. (2007). Telomere and telomerase in stem cells. British Journal of Cancer, 96(7), 1020–1024. https://doi.org/10.1038/sj.bjc.6603671

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Allsopp, R. (2012). Telomere length and iPSC reprogramming: Survival of the longest. Cell Research, 22(4), 614–615. https://doi.org/10.1038/cr.2012.6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Palm, W., & de Lange, T. (2008). How shelterin protects mammalian telomeres. Annual Review of Genetics, 42, 301–334. https://doi.org/10.1146/ANNUREV.GENET.41.110306.130350

    Article  CAS  PubMed  Google Scholar 

  88. Lingner, J., Hughes, T. R., Shevchenko, A., Mann, M., Lundblad, V., & Cech, T. R. (1997). Reverse transcriptase motifs in the catalytic subunit of telomerase. Science, 276(5312), 561–567. https://doi.org/10.1126/SCIENCE.276.5312.561

    Article  CAS  PubMed  Google Scholar 

  89. Cesare, A. J., & Reddel, R. R. (2010). Alternative lengthening of telomeres: Models, mechanisms and implications. Nature Reviews. Genetics, 11(5), 319–330. https://doi.org/10.1038/NRG2763

    Article  CAS  PubMed  Google Scholar 

  90. Fu, H., Tian, C.-l, Ye, X., Sheng, X., Wang, H., Liu, Y., & Liu, L. (2018). Dynamics of telomere rejuvenation during chemical induction to pluripotent stem cells. Stem Cell Reports, 11(1), 70. https://doi.org/10.1016/J.STEMCR.2018.05.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Lu, F., Liu, Y., Jiang, L., Yamaguchi, S., & Zhang, Y. (2014). Role of Tet proteins in enhancer activity and telomere elongation. Genes & Development, 28(19), 2103–2119. https://doi.org/10.1101/GAD.248005.114

    Article  CAS  Google Scholar 

  92. Cheng, Z. L., Zhang, M. L., Lin, H. P., Gao, C., Song, J. bin, Zheng, Z., …, & Ye, D. (2020). The Zscan4-Tet2 transcription nexus regulates metabolic rewiring and enhances proteostasis to promote reprogramming. Cell Reports, 32(2). https://doi.org/10.1016/J.CELREP.2020.107877

  93. Panopoulos, A. D., Yanes, O., Ruiz, S., Kida, Y. S., Diep, D., Tautenhahn, R., …, & Belmonte, J. C. I. (2012). The metabolome of induced pluripotent stem cells reveals metabolic changes occurring in somatic cell reprogramming. Cell Research, 22(1), 168–177. https://doi.org/10.1038/CR.2011.177

  94. Kwon, Y.-W., Paek, J.-S., Cho, H.-J., Lee, C.-S., Lee, H.-J., Park, I.-H., …, & Kim, H.-S. (2015). Role of Zscan4 in secondary murine iPSC derivation mediated by protein extracts of ESC or iPSC. Biomaterials. 59, 102-115. https://doi.org/10.1016/j.biomaterials.2015.03.031

  95. Su, R. J., Yang, Y., Neises, A., Payne, K. J., Wang, J., Viswanathan, K., …, & Zhang, X. B. (2013). Few single nucleotide variations in exomes of human cord blood induced pluripotent stem cells. PLoS One, 8(4). https://doi.org/10.1371/JOURNAL.PONE.0059908

  96. Siegl-Cachedenier, I., Flores, I., Klatt, P., & Blasco, M. A. (2007). Telomerase reverses epidermal hair follicle stem cell defects and loss of long-term survival associated with critically short telomeres. The Journal of Cell Biology, 179(2), 277. https://doi.org/10.1083/JCB.200704141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Park, H. S., Hwang, I., Choi, K. A., Jeong, H., Lee, J. Y., & Hong, S. (2015). Generation of induced pluripotent stem cells without genetic defects by small molecules. Biomaterials, 39, 47–58. https://doi.org/10.1016/J.BIOMATERIALS.2014.10.055

    Article  CAS  PubMed  Google Scholar 

  98. Sun, H., Kim, P., Jia, P., Park, A. K., Liang, H., & Zhao, Z. (2019). Distinct telomere length and molecular signatures in seminoma and non-seminoma of testicular germ cell tumor. Briefings in Bioinformatics, 20(4), 1502–1512. https://doi.org/10.1093/BIB/BBY020

    Article  CAS  PubMed  Google Scholar 

  99. Zhang, B., Fu, D., Xu, Q., Cong, X., Wu, C., Zhong, X., …, & Sun, Y. (2018). The senescence-associated secretory phenotype is potentiated by feedforward regulatory mechanisms involving Zscan4 and TAK1. Nature Communications, 9(1). https://doi.org/10.1038/S41467-018-04010-4

  100. Haridhasapavalan, K. K., Raina, K., Dey, C., Adhikari, P., & Thummer, R. P. (2020). An insight into reprogramming barriers to iPSC generation. Stem Cell Reviews and Reports, 16(1), 56–81. https://doi.org/10.1007/S12015-019-09931-1

    Article  PubMed  Google Scholar 

  101. Sundaravadivelu, P. K., Raina, K., Thool, M., Ray, A., Joshi, J. M., Kaveeshwar, V., …, & Thummer, R. P. (2021). Tissue-restricted stem cells as starting cell source for efficient generation of pluripotent stem cells: An overview. Advances in Experimental Medicine and Biology. https://doi.org/10.1007/5584_2021_660

  102. Ray, A., Joshi, J. M., Sundaravadivelu, P. K., Raina, K., Lenka, N., Kaveeshwar, V., & Thummer, R. P. (2021). An overview on promising somatic cell sources utilized for the efficient generation of induced pluripotent stem cells. Stem Cell Reviews and Reports, 17(6), 1954–1974. https://doi.org/10.1007/S12015-021-10200-3

    Article  PubMed  Google Scholar 

  103. Dey, C., Raina, K., Haridhasapavalan, K. K., Thool, M., Sundaravadivelu, P. K., Adhikari, P., …, & Thummer, R. P. (2021). An overview of reprogramming approaches to derive integration-free induced pluripotent stem cells for prospective biomedical applications. Recent Advances in iPSC Technology, 231–287. https://doi.org/10.1016/B978-0-12-822231-7.00011-4

  104. Borgohain, M. P., Haridhasapavalan, K. K., Dey, C., Adhikari, P., & Thummer, R. P. (2019). An insight into DNA-free reprogramming approaches to generate integration-free induced pluripotent stem cells for prospective biomedical applications. Stem Cell Reviews and Reports, 15(2), 286–313. https://doi.org/10.1007/S12015-018-9861-6

    Article  CAS  PubMed  Google Scholar 

  105. Haridhasapavalan, K. K., Borgohain, M. P., Dey, C., Saha, B., Narayan, G., Kumar, S., & Thummer, R. P. (2019). An insight into non-integrative gene delivery approaches to generate transgene-free induced pluripotent stem cells. Gene, 686, 146–159. https://doi.org/10.1016/J.GENE.2018.11.069

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

We thank all the members of the Laboratory for Stem Cell Engineering and Regenerative Medicine (SCERM) for their excellent support. This work was supported by North Eastern Region – Biotechnology Programme Management Cell (NERBPMC), Department of Biotechnology, Government of India (BT/PR16655/NER/95/132/2015), and also by IIT Guwahati Institutional Top-Up on Strat-Up Grant.

Author information

Author notes

  1. Madhuri Thool and Pradeep Kumar Sundaravadivelu: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory for Stem Cell Engineering and Regenerative Medicine, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, 781039, Guwahati, Assam, India

    Madhuri Thool, Pradeep Kumar Sundaravadivelu & Rajkumar P. Thummer

  2. Department of Biotechnology, National Institute of Pharmaceutical Education and Research Guwahati, Changsari, 781101, Guwahati, Assam, India

    Madhuri Thool & S. Sudhagar

Authors
  1. Madhuri Thool
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pradeep Kumar Sundaravadivelu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S. Sudhagar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rajkumar P. Thummer
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

MT and PKS wrote the original draft of the manuscript under the guidance of SS and RPT. SS and RPT reviewed and edited the draft. All authors read and approved the final draft of the manuscript.

Corresponding author

Correspondence to Rajkumar P. Thummer.

Ethics declarations

Ethics Approval

Not applicable

Consent to Participate

Not applicable

Consent to Publish

Not applicable

Research Involving Human Participants and/or Animals

None

Competing Interests

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

Additional information

Publisher's Note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Thool, M., Sundaravadivelu, P.K., Sudhagar, S. et al. A Comprehensive Review on the Role of ZSCAN4 in Embryonic Development, Stem Cells, and Cancer. Stem Cell Rev and Rep 18, 2740–2756 (2022). https://doi.org/10.1007/s12015-022-10412-1

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12015-022-10412-1

Keywords

Search

Navigation