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The Kleisin Subunits of Cohesin Are Involved in the Fate Determination of Embryonic Stem Cells

  • Received : 2021.12.09
  • Accepted : 2022.07.24
  • Published : 2022.11.30

Abstract

As a potential candidate to generate an everlasting cell source to treat various diseases, embryonic stem cells are regarded as a promising therapeutic tool in the regenerative medicine field. Cohesin, a multi-functional complex that controls various cellular activities, plays roles not only in organizing chromosome dynamics but also in controlling transcriptional activities related to self-renewal and differentiation of stem cells. Here, we report a novel role of the α-kleisin subunits of cohesin (RAD21 and REC8) in the maintenance of the balance between these two stem-cell processes. By knocking down REC8, RAD21, or the non-kleisin cohesin subunit SMC3 in mouse embryonic stem cells, we show that reduction in cohesin level impairs their self-renewal. Interestingly, the transcriptomic analysis revealed that knocking down each cohesin subunit enables the differentiation of embryonic stem cells into specific lineages. Specifically, embryonic stem cells in which cohesin subunit RAD21 were knocked down differentiated into cells expressing neural alongside germline lineage markers. Thus, we conclude that cohesin appears to control the fate determination of embryonic stem cells.

Keywords

Acknowledgement

This work was supported by grants from the National Research Foundation of Korea, funded by the Ministry of Science, ICT & Future Planning (No. 2020R1A2C2011887; 2018R1D1A1B07050755), the Korea Environment Industry & Technology Institute through "Digital Infrastructure Building Project for Monitoring, Surveying and Evaluating the Environmental Health Program (No. 2021003330007)" funded by Korea Ministry of Environment, and the BioGreen 21 Program (No. PJ015708) funded by Rural Development Administration, Republic of Korea.

References

  1. Betancourt, J., Katzman, S., and Chen, B. (2014). Nuclear factor one B regulates neural stem cell differentiation and axonal projection of corticofugal neurons. J. Comp. Neurol. 522, 6-35. https://doi.org/10.1002/cne.23373
  2. Biswas, U., Hempel, K., Llano, E., Pendas, A., and Jessberger, R. (2016). Distinct roles of meiosis-specific cohesin complexes in mammalian spermatogenesis. PLoS Genet. 12, e1006389. https://doi.org/10.1371/journal.pgen.1006389
  3. Brooker, A.S. and Berkowitz, K.M. (2014). The roles of cohesins in mitosis, meiosis, and human health and disease. Methods Mol. Biol. 1170, 229-266. https://doi.org/10.1007/978-1-4939-0888-2_11
  4. Choi, E.H., Yoon, S., Hahn, Y., and Kim, K.P. (2017). Cellular dynamics of Rad51 and Rad54 in response to postreplicative stress and DNA damage in HeLa cells. Mol. Cells, 40, 143-150. https://doi.org/10.14348/molcells.2017.2275
  5. Choi, E.H., Yoon, S., Koh, Y.E., Hong, T.K., Do, J.T., Lee, B.K., Hahn, Y., and Kim, K.P. (2022). Meiosis-specific cohesin complexes display essential and distinct roles in mitotic embryonic stem cell chromosomes. Genome Biol. 23, 70. https://doi.org/10.1186/s13059-022-02632-y
  6. Choi, E.H., Yoon, S., Koh, Y.E., Seo, Y.J., and Kim, K.P. (2020). Maintenance of genome integrity and active homologous recombination in embryonic stem cells. Exp. Mol. Med. 52, 1220-1229. https://doi.org/10.1038/s12276-020-0481-2
  7. Choumerianou, D.M., Dimitriou, H., and Kalmanti, M. (2008). Stem cells: promises versus limitations. Tissue Eng. Part B Rev. 14, 53-60. https://doi.org/10.1089/teb.2007.0216
  8. Cuartero, S., Weiss, F.D., Dharmalingam, G., Guo, Y., Ing-Simmons, E., Masella, S., Robles-Rebollo, I., Xiao, X., Wang, Y.F., Barozzi, I., et al. (2018). Control of inducible gene expression links cohesin to hematopoietic progenitor self-renewal and differentiation. Nat. Immunol. 19, 932-941. https://doi.org/10.1038/s41590-018-0184-1
  9. Efthymiou, A.G., Chen, G., Rao, M., Chen, G., and Boehm, M. (2014). Selfrenewal and cell lineage differentiation strategies in human embryonic stem cells and induced pluripotent stem cells. Expert Opin. Biol. Ther. 14, 1333-1344. https://doi.org/10.1517/14712598.2014.922533
  10. Findikli, N., Candan, N.Z., and Kahraman, S. (2006). Human embryonic stem cell culture: current limitations and novel strategies. Reprod. Biomed. Online 13, 581-590. https://doi.org/10.1016/S1472-6483(10)60648-7
  11. Frost, R.J., Hamra, F.K., Richardson, J.A., Qi, X., Bassel-Duby, R., and Olson, E.N. (2010). MOV10L1 is necessary for protection of spermatocytes against retrotransposons by Piwi-interacting RNAs. Proc. Natl. Acad. Sci. U. S. A. 107, 11847-11852. https://doi.org/10.1073/pnas.1007158107
  12. Galeev, R., Baudet, A., Kumar, P., Rundberg Nilsson, A., Nilsson, B., Soneji, S., Torngren, T., Borg, A., Kvist, A., and Larsson, J. (2016). Genomewide RNAi screen identifies cohesin genes as modifiers of renewal and differentiation in human HSCs. Cell Rep. 14, 2988-3000. https://doi.org/10.1016/j.celrep.2016.02.082
  13. Gamage, T.K., Chamley, L.W., and James, J.L. (2016). Stem cell insights into human trophoblast lineage differentiation. Hum. Reprod. Update 23, 77-103. https://doi.org/10.1093/humupd/dmw026
  14. Gao, Z., Ure, K., Ables, J.L., Lagace, D.C., Nave, K.A., Goebbels, S., Eisch, A.J., and Hsieh, J. (2009). Neurod1 is essential for the survival and maturation of adult-born neurons. Nat. Neurosci. 12, 1090-1092. https://doi.org/10.1038/nn.2385
  15. Gorecka, J., Kostiuk, V., Fereydooni, A., Gonzalez, L., Luo, J., Dash, B., Isaji, T., Ono, S., Liu, S., Lee, S.R., et al. (2019). The potential and limitations of induced pluripotent stem cells to achieve wound healing. Stem Cell Res. Ther. 10, 87. https://doi.org/10.1186/s13287-019-1185-1
  16. Haering, C.H. and Jessberger, R. (2012). Cohesin in determining chromosome architecture. Exp. Cell Res. 318, 1386-1393. https://doi.org/10.1016/j.yexcr.2012.03.016
  17. Han, S., Lee, H., Lee, A.J., Kim, S., Jung, I., Koh, G.Y., Kim, T., and Lee, D. (2021). CHD4 conceals aberrant CTCF-Binding sites at TAD interiors by regulating chromatin accessibility in mouse embryonic stem cells. Mol. Cells 44, 805-829. https://doi.org/10.14348/molcells.2021.0224
  18. Heng, B.C., Cao, T., and Lee, E.H. (2004). Directing stem cell differentiation into the chondrogenic lineage in vitro. Stem Cells 22, 1152-1167. https://doi.org/10.1634/stemcells.2004-0062
  19. Hirano, T. (2015). Chromosome dynamics during mitosis. Cold Spring Harb. Perspect. Biol. 7, a015792. https://doi.org/10.1101/cshperspect.a015792
  20. Hong, S., Joo, J.H., Yun, H., and Kim, K. (2019). The nature of meiotic chromosome dynamics and recombination in budding yeast. J. Microbiol. 57, 221-231. https://doi.org/10.1007/s12275-019-8541-9
  21. Ishiguro, K. (2019). The cohesin complex in mammalian meiosis. Genes Cells 24, 6-30. https://doi.org/10.1111/gtc.12652
  22. Kagey, M.H., Newman, J.J., Bilodeau, S., Zhan, Y., Orlando, D.A., van Berkum, N.L., Ebmeier, C.C., Goossens, J., Rahl, P.B., Levine, S.S., et al. (2010). Mediator and cohesin connect gene expression and chromatin architecture. Nature 467, 430-435. https://doi.org/10.1038/nature09380
  23. Keller, G. (2005). Embryonic stem cell differentiation: emergence of a new era in biology and medicine. Genes Dev. 19, 1129-1155. https://doi.org/10.1101/gad.1303605
  24. Khaminets, A., Ronnen-Oron, T., Baldauf, M., Meier, E., and Jasper, H. (2020). Cohesin controls intestinal stem cell identity by maintaining association of Escargot with target promoters. Elife 9, e48160. https://doi.org/10.7554/eLife.48160
  25. Li, S., Wei, X., He, J., Tian, X., Yuan, S., and Sun, L. (2018). Plasminogen activator inhibitor-1 in cancer research. Biomed. Pharmacother. 105, 83-94. https://doi.org/10.1016/j.biopha.2018.05.119
  26. Ma, H.T., Niu, C.M., Xia, J., Shen, X.Y., Xia, M.M., Hu, Y.Q., and Zheng, Y. (2018). Stimulated by retinoic acid gene 8 (Stra8) plays important roles in many stages of spermatogenesis. Asian J. Androl. 20, 479-487. https://doi.org/10.4103/aja.aja_26_18
  27. Mazzola, M., Deflorian, G., Pezzotta, A., Ferrari, L., Fazio, G., Bresciani, E., Saitta, C., Ferrari, L., Fumagalli, M., Parma, M., et al. (2019). NIPBL: a new player in myeloid cell differentiation. Haematologica 104, 1332-1341. https://doi.org/10.3324/haematol.2018.200899
  28. Mehta, G.D., Rizvi, S.M., and Ghosh, S.K. (2012). Cohesin: a guardian of genome integrity. Biochim. Biophys. Acta 1823, 1324-1342. https://doi.org/10.1016/j.bbamcr.2012.05.027
  29. Murry, C.E. and Keller, G. (2008). Differentiation of embryonic stem cells to clinically relevant populations: lessons from embryonic development. Cell 132, 661-680. https://doi.org/10.1016/j.cell.2008.02.008
  30. Nasmyth, K. and Haering, C.H. (2009). Cohesin: its roles and mechanisms. Annu. Rev. Genet. 43, 525-558. https://doi.org/10.1146/annurev-genet-102108-134233
  31. Nicholls, P.K., Schorle, H., Naqvi, S., Hu, Y.C., Fan, Y., Carmell, M.A., Dobrinski, I., Watson, A.L., Carlson, D.F., Fahrenkrug, S.C., et al. (2019). Mammalian germ cells are determined after PGC colonization of the nascent gonad. Proc. Natl. Acad. Sci. U. S. A. 116, 25677-25687. https://doi.org/10.1073/pnas.1910733116
  32. Noutsou, M., Li, J., Ling, J., Jones, J., Wang, Y., Chen, Y., and Sen, G.L. (2017). The cohesin complex is necessary for epidermal progenitor cell function through maintenance of self-renewal genes. Cell Rep. 20, 3005-3013. https://doi.org/10.1016/j.celrep.2017.09.003
  33. Park, M.H., Kim, A.K., Manandhar, S., Oh, S.Y., Jang, G.H., Kang, L., Lee, D.W., Hyeon, D.Y., Lee, S.H., Lee, H.E., et al. (2019). CCN1 interlinks integrin and hippo pathway to autoregulate tip cell activity. Elife 8, e46012. https://doi.org/10.7554/eLife.46012
  34. Patino, G.A., Claes, L.R., Lopez-Santiago, L.F., Slat, E.A., Dondeti, R.S., Chen, C., O'Malley, H.A., Gray, C.B., Miyazaki, H., Nukina, N., et al. (2009). A functional null mutation of SCN1B in a patient with Dravet syndrome. J. Neurosci. 29, 10764-10778. https://doi.org/10.1523/JNEUROSCI.2475-09.2009
  35. Peters, J.M., Tedeschi, A., and Schmitz, J. (2008). The cohesin complex and its roles in chromosome biology. Genes Dev. 22, 3089-3114. https://doi.org/10.1101/gad.1724308
  36. Poon, J., Wessel, G.M., and Yajima, M. (2016). An unregulated regulator: Vasa expression in the development of somatic cells and in tumorigenesis. Dev. Biol. 415, 24-32. https://doi.org/10.1016/j.ydbio.2016.05.012
  37. Potter, C.M., Lao, K.H., Zeng, L., and Xu, Q. (2014). Role of biomechanical forces in stem cell vascular lineage differentiation. Arterioscler. Thromb. Vasc. Biol. 34, 2184-2190. https://doi.org/10.1161/ATVBAHA.114.303423
  38. Revenkova, E., Eijpe, M., Heyting, C., Hodges, C.A., Hunt, P.A., Liebe, B., Scherthan, H., and Jessberger, R. (2004). Cohesin SMC1 beta is required for meiotic chromosome dynamics, sister chromatid cohesion and DNA recombination. Nat. Cell Biol. 6, 555-562. https://doi.org/10.1038/ncb1135
  39. Sasca, D., Yun, H., Giotopoulos, G., Szybinski, J., Evan, T., Wilson, N.K., Gerstung, M., Gallipoli, P., Green, A.R., Hills, R., et al. (2019). Cohesindependent regulation of gene expression during differentiation is lost in cohesin-mutated myeloid malignancies. Blood 134, 2195-2208.
  40. Sobhani, A., Khanlarkhani, N., Baazm, M., Mohammadzadeh, F., Najafi, A., Mehdinejadiani, S., and Sargolzaei Aval, F. (2017). Multipotent stem cell and current application. Acta Med. Iran. 55, 6-23.
  41. Sofueva, S., Yaffe, E., Chan, W.C., Georgopoulou, D., Vietri Rudan, M., Mira-Bontenbal, H., Pollard, S.M., Schroth, G.P., Tanay, A., and Hadjur, S. (2013). Cohesin-mediated interactions organize chromosomal domain architecture. EMBO J. 32, 3119-3129. https://doi.org/10.1038/emboj.2013.237
  42. Steinbeck, J.A. and Studer, L. (2015). Moving stem cells to the clinic: potential and limitations for brain repair. Neuron 86, 187-206. https://doi.org/10.1016/j.neuron.2015.03.002
  43. Subramanian, V., Klattenhoff, C.A., and Boyer, L.A. (2009). Screening for novel regulators of embryonic stem cell identity. Cell Stem Cell 4, 377-378. https://doi.org/10.1016/j.stem.2009.04.006
  44. Suzuki, S., Namiki, J., Shibata, S., Mastuzaki, Y., and Okano, H. (2010). The neural stem/progenitor cell marker nestin is expressed in proliferative endothelial cells, but not in mature vasculature. J. Histochem. Cytochem. 58, 721-730. https://doi.org/10.1369/jhc.2010.955609
  45. Takahashi, K. and Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663-676. https://doi.org/10.1016/j.cell.2006.07.024
  46. Takigawa, M. (2013). CCN2: a master regulator of the genesis of bone and cartilage. J. Cell Commun. Signal. 7, 191-201. https://doi.org/10.1007/s12079-013-0204-8
  47. Vazin, T. and Freed, W.J. (2010). Human embryonic stem cells: derivation, culture, and differentiation: a review. Restor. Neurol. Neurosci. 28, 589-603.
  48. Viny, A.D., Bowman, R.L., Liu, Y., Lavallee, V.P., Eisman, S.E., Xiao, W., Durham, B.H., Navitski, A., Park, J., Braunstein, S., et al. (2019). Cohesin members Stag1 and Stag2 display distinct roles in chromatin accessibility and topological control of HSC self-renewal and differentiation. Cell Stem Cell 25, 682-696.e8. https://doi.org/10.1016/j.stem.2019.08.003
  49. Walker, E., Ohishi, M., Davey, R.E., Zhang, W., Cassar, P.A., Tanaka, T.S., Der, S.D., Morris, Q., Hughes, T.R., Zandstra, P.W., et al. (2007). Prediction and testing of novel transcriptional networks regulating embryonic stem cell self-renewal and commitment. Cell Stem Cell 1, 71-86. https://doi.org/10.1016/j.stem.2007.04.002
  50. Willerth, S.M., Arendas, K.J., Gottlieb, D.I., and Sakiyama-Elbert, S.E. (2006). Optimization of fibrin scaffolds for differentiation of murine embryonic stem cells into neural lineage cells. Biomaterials 27, 5990-6003. https://doi.org/10.1016/j.biomaterials.2006.07.036
  51. Xu, B., Bai, Z., Yin, J., and Zhang, Z. (2019). Global transcriptomic analysis identifies SERPINE1 as a prognostic biomarker associated with epithelialto-mesenchymal transition in gastric cancer. PeerJ 7, e7091. https://doi.org/10.7717/peerj.7091
  52. Young, R.A. (2011). Control of the embryonic stem cell state. Cell 144, 940-954. https://doi.org/10.1016/j.cell.2011.01.032
  53. Zakrzewski, W., Dobrzynski, M., Szymonowicz, M., and Rybak, Z. (2019). Stem cells: past, present, and future. Stem Cell Res. Ther. 10, 68. https://doi.org/10.1186/s13287-019-1165-5
  54. Zhang, H. and Wang, Z.Z. (2008). Mechanisms that mediate stem cell selfrenewal and differentiation. J. Cell. Biochem. 103, 709-718. https://doi.org/10.1002/jcb.21460