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.
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References
1.
MeyneJ, RatliffRL and MoyzisRK. (1989). Conservation of the human telomere sequence (TTAGGG)n among vertebrates. Proc Natl Acad Sci U S A, 86:7049–7053.
2.
AutexierC and LueNF. (2006). The structure and function of telomerase reverse transcriptase. Annu Rev Biochem, 75:493–517.
3.
LiuL, BaileySM, OkukaM, MuñozP, LiC, ZhouL, WuC, CzerwiecE, SandlerL, et al. (2007). Telomere lengthening early in development. Nat Cell Biol, 9:1436–1441.
4.
PucciF, GardanoL and HarringtonL. (2013). Short telomeres in ESCs lead to unstable differentiation. Cell Stem Cell, 12:479–486.
5.
LührigS, SiamishiI, Tesmer-WolfM, ZechnerU, EngelW and NolteJ. (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.
OlsonMO, KirsteinMN and WallaceMO. (1990). Limited proteolysis as a probe of the conformation and nucleic acid binding regions of nucleolin. Biochemistry, 29:5682–5686.
8.
KhurtsS, MasutomiK, DelgermaaL, AraiK, OishiN, MizunoH, HayashiN, HahnWC and MurakamiS. (2004). Nucleolin interacts with telomerase. J Biol Chem, 279:51508–51515.
9.
WongJMY, KusdraL and CollinsK. (2002). Subnuclear shuttling of human telomerase induced by transformation and DNA damage. Nat Cell Biol, 4:731–736.
10.
JohanssonH, SvenssonF, RunnbergR, SimonssonT and SimonssonS. (2010). Phosphorylated nucleolin interacts with translationally controlled tumor protein during mitosis and with Oct4 during interphase in ES cells. PLoS One, 5:e13678.
11.
JohanssonH and SimonssonS. (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.
CoddV, ManginoM, van der HarstP, BraundPS, KaiserM, BeveridgeAJ, RafeltS, MooreJ, NelsonC, et al. (2010). Common variants near TERC are associated with mean telomere length. Nat Genet, 42:197–199.
14.
CoddV, NelsonCP, AlbrechtE, ManginoM, DeelenJ, BuxtonJL, HottengaJJ, FischerK, EskoT, et al. (2013). Identification of seven loci affecting mean telomere length and their association with disease. Nat Genet, 45:422–427, 427e1–2.
15.
CouttsF, PalmosAB, DuarteRRR, de JongS, LewisCM, DimaD and PowellTR. (2019). The polygenic nature of telomere length and the anti-ageing properties of lithium. Neuropsychopharmacology, 44:757–765.
16.
CallicottRJ and WomackJE. (2006). Real-time PCR assay for measurement of mouse telomeres. Comp Med, 56:17–22.
17.
SkarnesWC, RosenB, WestAP, KoutsourakisM, BushellW, IyerV, MujicaAO, ThomasM, HarrowJ, et al. (2011). A conditional knockout resource for the genome-wide study of mouse gene function. Nature, 474:337–342.
18.
StarlingJA, MauleJ, HastieND and AllshireRC. (1990). Extensive telomere repeat arrays in mouse are hypervariable. Nucleic Acids Res, 18:6881–6888.
19.
ZhuL, HathcockKS, HandeP, LansdorpPM, SeldinMF and HodesRJ. (1998). Telomere length regulation in mice is linked to a novel chromosome locus. Proc Natl Acad Sci U S A, 95:8648–8653.
20.
LiF, GeY, LiuD and SongyangZ. (2020). The role of telomere-binding modulators in pluripotent stem cells. Protein Cell, 11:60–70.
21.
HuangY, LiangP, LiuD, HuangJ and SongyangZ. (2014). Telomere regulation in pluripotent stem cells. Protein Cell, 5:194–202.
SchindelinJ, Arganda-CarrerasI, FriseE, KaynigV, LongairM, PietzschT, PreibischS, RuedenC, SaalfeldS, et al. (2012). Fiji: an open-source platform for biological-image analysis. Nat Methods, 9:676–682.
24.
ZengF, BaldwinDA and SchultzRM. (2004). Transcript profiling during preimplantation mouse development. Dev Biol, 272:483–496.
25.
ZhaoS, WangF and LiuL. (2019). Alternative lengthening of telomeres (ALT) in tumors and pluripotent stem cells. Genes, 10:1030.
26.
WangH, ZhangK, LiuY, FuY, GaoS, GongP, WangH, ZhouZ, ZengM, 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-TerronesD, GaumeX, IshiuchiT, WeissA, KoppA, KruseK, PenningA, VaquerizasJM, BrinoL and Torres-PadillaM-E. (2018). A molecular roadmap for the emergence of early-embryonic-like cells in culture. Nat Genet, 50:106–119.
28.
FalcoG, LeeS-L, StanghelliniI, BasseyUC, HamataniT and KoMSH. (2007). Zscan4: a novel gene expressed exclusively in late 2-cell embryos and embryonic stem cells. Dev Biolgy, 307:539–550.
29.
ZalzmanM, FalcoG, SharovaLV, NishiyamaA, ThomasM, LeeS-L, StaggCA, HoangHG, YangH-T, et al. (2010). Zscan4 regulates telomere elongation and genomic stability in ES cells. Nature, 464:858–863.
30.
ZhangQ, DanJ, WangH, GuoR, MaoJ, FuH, WeiX and LiuL. (2016). Tcstv1 and Tcstv3 elongate telomeres of mouse ES cells. Sci Rep, 6:19852.
31.
ZengS, LiuL, SunY, XieP, HuL, YuanD, ChenD, OuyangQ, LinG and LuG. (2014). Telomerase-mediated telomere elongation from human blastocysts to embryonic stem cells. J Cell Sci, 127:752–762.
32.
CeruloL, TagliaferriD, MarottaP, ZoppoliP, RussoF, MazioC, DeFeliceM, CeccarelliM and FalcoG. (2014). Identification of a novel gene signature of ES cells self-renewal fluctuation through system-wide analysis. PLoS One, 9:e83235.
33.
WongC-W, HouP-S, TsengS-F, ChienC-L, WuK-J, ChenH-F, HoH-N, KyoS and TengS-C. (2010). Krüppel-like transcription factor 4 contributes to maintenance of telomerase activity in stem cells. Stem Cells, 28:1510–1517.
34.
HidemaS, FukudaT, DateS, TokitakeY, MatsuiY, SasakiH and NishimoriK. (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.
OuJH, LiYR, WangZP, JinC, LiK, LuY, ZouDF, LiPY, LiMZ, 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.
PechMF, GarbuzovA, HasegawaK, SukhwaniM, ZhangRJ, BenayounBA, BrockmanSA, LinS, BrunetA, OrwigKE and ArtandiSE. (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.
AchiMV, RavindranathN and DymM. (2000). Telomere length in male germ cells is inversely correlated with telomerase activity. Biol Reprod, 63:591–598.
38.
WangC, ZhaoL and LuS. (2015). Role of TERRA in the regulation of telomere length. Int J Biol Sci, 11:316–323.
39.
ZhuX, KumarR, MandalM, SharmaN, SharmaHW, DhingraU, SokoloskiJA, HsiaoR and NarayananR. (1996). Cell cycle-dependent modulation of telomerase activity in tumor cells. Proc Natl Acad Sci U S A, 93:6091–6095.
40.
LeeFS and ValleeBL. (1993). Structure and action of mammalian ribonuclease (angiogenin) inhibitor. Prog Nucleic Acid Res Mol Biol, 44:1–30.
41.
Okumura-NakanishiS, SaitoM, NiwaH and IshikawaF. (2005). Oct-3/4 and Sox2 regulate Oct-3/4 gene in embryonic stem cells. J Biol Chem, 280:5307–5317.
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