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http://dx.doi.org/10.14348/molcells.2022.2042

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

Koh, Young Eun (Department of Life Sciences, Chung-Ang University)
Choi, Eui-Hwan (Department of Life Sciences, Chung-Ang University)
Kim, Jung-Woong (Department of Life Sciences, Chung-Ang University)
Kim, Keun Pil (Department of Life Sciences, Chung-Ang University)
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
cohesin; embryonic stem cells; RAD21; REC8; trascriptomic analysis;
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1 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.   DOI
2 Young, R.A. (2011). Control of the embryonic stem cell state. Cell 144, 940-954.   DOI
3 Zhang, H. and Wang, Z.Z. (2008). Mechanisms that mediate stem cell selfrenewal and differentiation. J. Cell. Biochem. 103, 709-718.   DOI
4 Keller, G. (2005). Embryonic stem cell differentiation: emergence of a new era in biology and medicine. Genes Dev. 19, 1129-1155.   DOI
5 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.   DOI
6 Murry, C.E. and Keller, G. (2008). Differentiation of embryonic stem cells to clinically relevant populations: lessons from embryonic development. Cell 132, 661-680.   DOI
7 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.   DOI
8 Vazin, T. and Freed, W.J. (2010). Human embryonic stem cells: derivation, culture, and differentiation: a review. Restor. Neurol. Neurosci. 28, 589-603.
9 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.   DOI
10 Zakrzewski, W., Dobrzynski, M., Szymonowicz, M., and Rybak, Z. (2019). Stem cells: past, present, and future. Stem Cell Res. Ther. 10, 68.   DOI
11 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.   DOI
12 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.   DOI
13 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.   DOI
14 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.   DOI
15 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.   DOI
16 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.   DOI
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.   DOI
18 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.   DOI
19 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.   DOI
20 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.   DOI
21 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.   DOI
22 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.   DOI
23 Choumerianou, D.M., Dimitriou, H., and Kalmanti, M. (2008). Stem cells: promises versus limitations. Tissue Eng. Part B Rev. 14, 53-60.   DOI
24 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.   DOI
25 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.   DOI
26 Peters, J.M., Tedeschi, A., and Schmitz, J. (2008). The cohesin complex and its roles in chromosome biology. Genes Dev. 22, 3089-3114.   DOI
27 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.   DOI
28 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.   DOI
29 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.   DOI
30 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.   DOI
31 Haering, C.H. and Jessberger, R. (2012). Cohesin in determining chromosome architecture. Exp. Cell Res. 318, 1386-1393.   DOI
32 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.   DOI
33 Hirano, T. (2015). Chromosome dynamics during mitosis. Cold Spring Harb. Perspect. Biol. 7, a015792.   DOI
34 Ishiguro, K. (2019). The cohesin complex in mammalian meiosis. Genes Cells 24, 6-30.   DOI
35 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.   DOI
36 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.   DOI
37 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.   DOI
38 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.   DOI
39 Mehta, G.D., Rizvi, S.M., and Ghosh, S.K. (2012). Cohesin: a guardian of genome integrity. Biochim. Biophys. Acta 1823, 1324-1342.   DOI
40 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.   DOI
41 Nasmyth, K. and Haering, C.H. (2009). Cohesin: its roles and mechanisms. Annu. Rev. Genet. 43, 525-558.   DOI
42 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.   DOI
43 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.   DOI
44 Steinbeck, J.A. and Studer, L. (2015). Moving stem cells to the clinic: potential and limitations for brain repair. Neuron 86, 187-206.   DOI
45 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.   DOI
46 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.   DOI
47 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.
48 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.   DOI
49 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.
50 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.   DOI
51 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.   DOI
52 Takigawa, M. (2013). CCN2: a master regulator of the genesis of bone and cartilage. J. Cell Commun. Signal. 7, 191-201.   DOI
53 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.   DOI
54 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.   DOI