Research Article
No access
Published Online: 11 November 2021

Lrrc34 Interacts with Oct4 and Has an Impact on Telomere Length in Mouse Embryonic Stem Cells

Publication: Stem Cells and Development
Volume 30, Issue Number 22


Telomere length maintenance in pluripotent stem cells (PSCs) is a main characteristic and a major premise for their undifferentiated long-term survival. However, little is known about the factors that control telomere length and elongation in these cells. Here, I describe Lrrc34 (leucine-rich repeat 34) as a novel telomere length regulating gene in murine embryonic stem cells. Downregulation of Lrrc34 results in significant reduction of telomerase activity and telomere length over time while also influencing the expression of known telomere length-associated genes. Generating induced PSCs (iPSCs) with Lrrc34 as a fifth factor in classical Yamanaka reprogramming increases the efficiency but did not have an impact on telomere length in the resulting iPSCs. Moreover, Lrrc34 was found to interact with Oct4, connecting the pluripotency network to telomere length regulation.

Get full access to this article

View all available purchase options and get full access to this article.


1. Meyne J, RL Ratliff and RK Moyzis. (1989). Conservation of the human telomere sequence (TTAGGG)n among vertebrates. Proc Natl Acad Sci U S A 86:7049–7053.
2. Autexier C and NF Lue. (2006). The structure and function of telomerase reverse transcriptase. Annu Rev Biochem 75:493–517.
3. Liu L, SM Bailey, M Okuka, P Muñoz, C Li, L Zhou, C Wu, E Czerwiec, L Sandler, et al. (2007). Telomere lengthening early in development. Nat Cell Biol 9:1436–1441.
4. Pucci F, L Gardano and L Harrington. (2013). Short telomeres in ESCs lead to unstable differentiation. Cell Stem Cell 12:479–486.
5. Lührig S, I Siamishi, M Tesmer-Wolf, U Zechner, W Engel and J Nolte. (2014). Lrrc34, a novel nucleolar protein, interacts with npm1 and ncl and has an impact on pluripotent stem cells. Stem Cells Dev 23:2862–2874.
6. Lindström MS. (2011). NPM1/B23: a multifunctional chaperone in ribosome biogenesis and chromatin remodeling. Biochem Res Int 2011:195209.
7. Olson MO, MN Kirstein and MO Wallace. (1990). Limited proteolysis as a probe of the conformation and nucleic acid binding regions of nucleolin. Biochemistry 29:5682–5686.
8. Khurts S, K Masutomi, L Delgermaa, K Arai, N Oishi, H Mizuno, N Hayashi, WC Hahn and S Murakami. (2004). Nucleolin interacts with telomerase. J Biol Chem 279:51508–51515.
9. Wong JMY, L Kusdra and K Collins. (2002). Subnuclear shuttling of human telomerase induced by transformation and DNA damage. Nat Cell Biol 4:731–736.
10. Johansson H, F Svensson, R Runnberg, T Simonsson and S Simonsson. (2010). Phosphorylated nucleolin interacts with translationally controlled tumor protein during mitosis and with Oct4 during interphase in ES cells. PLoS One 5:e13678.
11. Johansson H and S Simonsson. (2010). Core transcription factors, Oct4, Sox2 and Nanog, individually form complexes with nucleophosmin (Npm1) to control embryonic stem (ES) cell fate determination. Aging 2:815–822.
12. Chiba K, JZ Johnson, JM Vogan, T Wagner, JM Boyle and D Hockemeyer. (2015). Cancer-associated TERT promoter mutations abrogate telomerase silencing. Elife 4: e07918.
13. Codd V, M Mangino, P van der Harst, PS Braund, M Kaiser, AJ Beveridge, S Rafelt, J Moore, C Nelson, et al. (2010). Common variants near TERC are associated with mean telomere length. Nat Genet 42:197–199.
14. Codd V, CP Nelson, E Albrecht, M Mangino, J Deelen, JL Buxton, JJ Hottenga, K Fischer, T Esko, et al. (2013). Identification of seven loci affecting mean telomere length and their association with disease. Nat Genet 45:422–427, 427e1–2.
15. Coutts F, AB Palmos, RRR Duarte, S de Jong, CM Lewis, D Dima and TR Powell. (2019). The polygenic nature of telomere length and the anti-ageing properties of lithium. Neuropsychopharmacology 44:757–765.
16. Callicott RJ and JE Womack. (2006). Real-time PCR assay for measurement of mouse telomeres. Comp Med 56:17–22.
17. Skarnes WC, B Rosen, AP West, M Koutsourakis, W Bushell, V Iyer, AO Mujica, M Thomas, J Harrow, et al. (2011). A conditional knockout resource for the genome-wide study of mouse gene function. Nature 474:337–342.
18. Starling JA, J Maule, ND Hastie and RC Allshire. (1990). Extensive telomere repeat arrays in mouse are hypervariable. Nucleic Acids Res 18:6881–6888.
19. Zhu L, KS Hathcock, P Hande, PM Lansdorp, MF Seldin and RJ Hodes. (1998). Telomere length regulation in mice is linked to a novel chromosome locus. Proc Natl Acad Sci U S A 95:8648–8653.
20. Li F, Y Ge, D Liu and Z Songyang. (2020). The role of telomere-binding modulators in pluripotent stem cells. Protein Cell 11:60–70.
21. Huang Y, P Liang, D Liu, J Huang and Z Songyang. (2014). Telomere regulation in pluripotent stem cells. Protein Cell 5:194–202.
22. Marion RM, K Strati, H Li, A Tejera, S Schoeftner, S Ortega, M Serrano and MA Blasco. (2009). Telomeres acquire embryonic stem cell characteristics in induced pluripotent stem cells. Cell Stem Cell 4:141–154.
23. Schindelin J, I Arganda-Carreras, E Frise, V Kaynig, M Longair, T Pietzsch, S Preibisch, C Rueden, S Saalfeld, et al. (2012). Fiji: an open-source platform for biological-image analysis. Nat Methods 9:676–682.
24. Zeng F, DA Baldwin and RM Schultz. (2004). Transcript profiling during preimplantation mouse development. Dev Biol 272:483–496.
25. Zhao S, F Wang and L Liu. (2019). Alternative lengthening of telomeres (ALT) in tumors and pluripotent stem cells. Genes 10:1030.
26. Wang H, K Zhang, Y Liu, Y Fu, S Gao, P Gong, H Wang, Z Zhou, M Zeng, et al. (2017). Telomere heterogeneity linked to metabolism and pluripotency state revealed by simultaneous analysis of telomere length and RNA-seq in the same human embryonic stem cell. BMC Biol 15:114.
27. Rodriguez-Terrones D, X Gaume, T Ishiuchi, A Weiss, A Kopp, K Kruse, A Penning, JM Vaquerizas, L Brino and M-E Torres-Padilla. (2018). A molecular roadmap for the emergence of early-embryonic-like cells in culture. Nat Genet 50:106–119.
28. Falco G, S-L Lee, I Stanghellini, UC Bassey, T Hamatani and MSH Ko. (2007). Zscan4: a novel gene expressed exclusively in late 2-cell embryos and embryonic stem cells. Dev Biolgy 307:539–550.
29. Zalzman M, G Falco, LV Sharova, A Nishiyama, M Thomas, S-L Lee, CA Stagg, HG Hoang, H-T Yang, et al. (2010). Zscan4 regulates telomere elongation and genomic stability in ES cells. Nature 464:858–863.
30. Zhang Q, J Dan, H Wang, R Guo, J Mao, H Fu, X Wei and L Liu. (2016). Tcstv1 and Tcstv3 elongate telomeres of mouse ES cells. Sci Rep 6:19852.
31. Zeng S, L Liu, Y Sun, P Xie, L Hu, D Yuan, D Chen, Q Ouyang, G Lin and G Lu. (2014). Telomerase-mediated telomere elongation from human blastocysts to embryonic stem cells. J Cell Sci 127:752–762.
32. Cerulo L, D Tagliaferri, P Marotta, P Zoppoli, F Russo, C Mazio, M DeFelice, M Ceccarelli and G Falco. (2014). Identification of a novel gene signature of ES cells self-renewal fluctuation through system-wide analysis. PLoS One 9:e83235.
33. Wong C-W, P-S Hou, S-F Tseng, C-L Chien, K-J Wu, H-F Chen, H-N Ho, S Kyo and S-C Teng. (2010). Krüppel-like transcription factor 4 contributes to maintenance of telomerase activity in stem cells. Stem Cells 28:1510–1517.
34. Hidema S, T Fukuda, S Date, Y Tokitake, Y Matsui, H Sasaki and K Nishimori. (2016). Transgenic expression of Telomerase reverse transcriptase (Tert) improves cell proliferation of primary cells and enhances reprogramming efficiency into the induced pluripotent stem cell. Biosci Biotechnol Biochem 80:1925–1933.
35. Ou JH, YR Li, ZP Wang, C Jin, K Li, Y Lu, DF Zou, PY Li, MZ Li, et al. (2020). Lrrc34 is highly expressed in SSCs and is necessary for SSC expansion in vitro. Chin Med Sci J 35:20–30.
36. Pech MF, A Garbuzov, K Hasegawa, M Sukhwani, RJ Zhang, BA Benayoun, SA Brockman, S Lin, A Brunet, KE Orwig and SE Artandi. (2015). High telomerase is a hallmark of undifferentiated spermatogonia and is required for maintenance of male germline stem cells. Genes Dev 29:2420–2434.
37. Achi MV, N Ravindranath and M Dym. (2000). Telomere length in male germ cells is inversely correlated with telomerase activity. Biol Reprod 63:591–598.
38. Wang C, L Zhao and S Lu. (2015). Role of TERRA in the regulation of telomere length. Int J Biol Sci 11:316–323.
39. Zhu X, R Kumar, M Mandal, N Sharma, HW Sharma, U Dhingra, JA Sokoloski, R Hsiao and R Narayanan. (1996). Cell cycle-dependent modulation of telomerase activity in tumor cells. Proc Natl Acad Sci U S A 93:6091–6095.
40. Lee FS and BL Vallee. (1993). Structure and action of mammalian ribonuclease (angiogenin) inhibitor. Prog Nucleic Acid Res Mol Biol 44:1–30.
41. Okumura-Nakanishi S, M Saito, H Niwa and F Ishikawa. (2005). Oct-3/4 and Sox2 regulate Oct-3/4 gene in embryonic stem cells. J Biol Chem 280:5307–5317.

Information & Authors


Published In

cover image Stem Cells and Development
Stem Cells and Development
Volume 30Issue Number 22November 2021
Pages: 1093 - 1102
PubMed: 34549596


Published in print: November 2021
Published online: 11 November 2021
Published ahead of print: 27 October 2021
Published ahead of production: 22 September 2021
Accepted: 16 September 2021
Received: 25 May 2021


Request permissions for this article.




    Jessica Nolte [email protected]
    Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany.


    Address correspondence to: Dr. Jessica Nolte, Institute of Human Genetics, University Medical Center Göttingen, Heinrich-Düker-Weg 12, Göttingen 37073, Germany [email protected]

    Author Disclosure Statement

    No competing financial interests exist.

    Funding Information

    This work was supported by the German Research Foundation (DFG) grant to Jessica Nolte (No. 941/4-1).

    Metrics & Citations



    Export citation

    Select the format you want to export the citations of this publication.

    View Options

    Get Access

    Access content

    To read the fulltext, please use one of the options below to sign in or purchase access.

    Society Access

    If you are a member of a society that has access to this content please log in via your society website and then return to this publication.

    Restore your content access

    Enter your email address to restore your content access:

    Note: This functionality works only for purchases done as a guest. If you already have an account, log in to access the content to which you are entitled.

    View options


    View PDF/ePub

    Full Text

    View Full Text







    Copy the content Link

    Share on social media

    Back to Top