BMAL1 associates with chromosome ends to control rhythms in TERRA and telomeric heterochromatin

Autoři: Jinhee Park aff001;  Qiaoqiao Zhu aff001;  Emily Mirek aff002;  Li Na aff001;  Hamidah Raduwan aff001;  Tracy G. Anthony aff002;  William J. Belden aff001
Působiště autorů: Department of Animal Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ, United States of America aff001;  Department of Nutritional Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ, United States of America aff002
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article


The circadian clock and aging are intertwined. Disruption to the normal diurnal rhythm accelerates aging and corresponds with telomere shortening. Telomere attrition also correlates with increase cellular senescence and incidence of chronic disease. In this report, we examined diurnal association of White Collar 2 (WC-2) in Neurospora and BMAL1 in zebrafish and mice and found that these circadian transcription factors associate with telomere DNA in a rhythmic fashion. We also identified a circadian rhythm in Telomeric Repeat-containing RNA (TERRA), a lncRNA transcribed from the telomere. The diurnal rhythm in TERRA was lost in the liver of Bmal1-/- mice indicating it is a circadian regulated transcript. There was also a BMAL1-dependent rhythm in H3K9me3 at the telomere in zebrafish brain and mouse liver, and this rhythm was lost with increasing age. Taken together, these results provide evidence that BMAL1 plays a direct role in telomere homeostasis by regulating rhythms in TERRA and heterochromatin. Loss of these rhythms may contribute to telomere erosion during aging.

Klíčová slova:

Circadian oscillators – Circadian rhythms – Mammalian genomics – Telomeres – Zebrafish – Heterochromatin – Neurospora – Northern blot


1. Wang XS, Armstrong ME, Cairns BJ, Key TJ, Travis RC. Shift work and chronic disease: the epidemiological evidence. Occup Med (Lond). 2011;61(2):78–89. doi: 10.1093/occmed/kqr001 21355031; PubMed Central PMCID: PMC3045028.

2. Bell-Pedersen D, Cassone VM, Earnest DJ, Golden SS, Hardin PE, Thomas TL, et al. Circadian rhythms from multiple oscillators: lessons from diverse organisms. Nat Rev Genet. 2005;6(7):544–56. Epub 2005/06/14. doi: 10.1038/nrg1633 15951747; PubMed Central PMCID: PMC2735866.

3. Hardin PE, Panda S. Circadian timekeeping and output mechanisms in animals. Curr Opin Neurobiol. 2013;23(5):724–31. Epub 2013/06/05. doi: 10.1016/j.conb.2013.02.018 23731779; PubMed Central PMCID: PMC3973145.

4. Schibler U, Sassone-Corsi P. A web of circadian pacemakers. Cell. 2002;111(7):919–22. Epub 2003/01/01. doi: 10.1016/s0092-8674(02)01225-4 12507418.

5. Partch CL, Green CB, Takahashi JS. Molecular architecture of the mammalian circadian clock. Trends Cell Biol. 2014;24(2):90–9. Epub 2013/08/07. doi: 10.1016/j.tcb.2013.07.002 23916625; PubMed Central PMCID: PMC3946763.

6. Aryal RP, Kwak PB, Tamayo AG, Gebert M, Chiu PL, Walz T, et al. Macromolecular Assemblies of the Mammalian Circadian Clock. Mol Cell. 2017;67(5):770–82 e6. doi: 10.1016/j.molcel.2017.07.017 28886335; PubMed Central PMCID: PMC5679067.

7. Duong HA, Robles MS, Knutti D, Weitz CJ. A molecular mechanism for circadian clock negative feedback. Science. 2011;332(6036):1436–9. Epub 2011/06/18. doi: 10.1126/science.1196766 21680841; PubMed Central PMCID: PMC3859310.

8. Duong HA, Weitz CJ. Temporal orchestration of repressive chromatin modifiers by circadian clock Period complexes. Nat Struct Mol Biol. 2014;21(2):126–32. Epub 2014/01/15. doi: 10.1038/nsmb.2746 24413057; PubMed Central PMCID: PMC4227600.

9. Park J, Belden WJ. Long non-coding RNAs have age-dependent diurnal expression that coincides with age-related changes in genome-wide facultative heterochromatin. BMC Genomics. 2018;19(1):777. doi: 10.1186/s12864-018-5170-3 30373515; PubMed Central PMCID: PMC6206985.

10. Dantzer F, Santoro R. The expanding role of PARPs in the establishment and maintenance of heterochromatin. FEBS J. 2013;280(15):3508–18. Epub 2013/06/05. doi: 10.1111/febs.12368 23731385.

11. Plath K, Mlynarczyk-Evans S, Nusinow DA, Panning B. Xist RNA and the mechanism of X chromosome inactivation. Annu Rev Genet. 2002;36:233–78. Epub 2002/11/14. doi: 10.1146/annurev.genet.36.042902.092433 12429693.

12. Schoeftner S, Blasco MA. A 'higher order' of telomere regulation: telomere heterochromatin and telomeric RNAs. EMBO J. 2009;28(16):2323–36. Epub 2009/07/25. doi: 10.1038/emboj.2009.197 19629032; PubMed Central PMCID: PMC2722253.

13. de Lange T. Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev. 2005;19(18):2100–10. Epub 2005/09/17. 19/18/2100 [pii] doi: 10.1101/gad.1346005 16166375.

14. Blackburn EH. Telomeres and telomerase: their mechanisms of action and the effects of altering their functions. FEBS Lett. 2005;579(4):859–62. Epub 2005/02/01. S0014-5793(04)01426-7 [pii] doi: 10.1016/j.febslet.2004.11.036 15680963.

15. Chavez A, Tsou AM, Johnson FB. Telomeres do the (un)twist: helicase actions at chromosome termini. Biochimica et biophysica acta. 2009;1792(4):329–40. doi: 10.1016/j.bbadis.2009.02.008 19245831; PubMed Central PMCID: PMC2670356.

16. Galati A, Micheli E, Cacchione S. Chromatin structure in telomere dynamics. Front Oncol. 2013;3:46. doi: 10.3389/fonc.2013.00046 23471416; PubMed Central PMCID: PMC3590461.

17. Roig I, Liebe B, Egozcue J, Cabero L, Garcia M, Scherthan H. Female-specific features of recombinational double-stranded DNA repair in relation to synapsis and telomere dynamics in human oocytes. Chromosoma. 2004;113(1):22–33. doi: 10.1007/s00412-004-0290-8 15235794.

18. Perrini B, Piacentini L, Fanti L, Altieri F, Chichiarelli S, Berloco M, et al. HP1 controls telomere capping, telomere elongation, and telomere silencing by two different mechanisms in Drosophila. Mol Cell. 2004;15(3):467–76. doi: 10.1016/j.molcel.2004.06.036 15304225.

19. Azzalin CM, Reichenbach P, Khoriauli L, Giulotto E, Lingner J. Telomeric repeat containing RNA and RNA surveillance factors at mammalian chromosome ends. Science. 2007;318(5851):798–801. Epub 2007/10/06. 1147182 [pii] doi: 10.1126/science.1147182 17916692.

20. Chu HP, Cifuentes-Rojas C, Kesner B, Aeby E, Lee HG, Wei C, et al. TERRA RNA Antagonizes ATRX and Protects Telomeres. Cell. 2017;170(1):86–101 e16. doi: 10.1016/j.cell.2017.06.017 28666128; PubMed Central PMCID: PMC5552367.

21. Lopez de Silanes I, Grana O, De Bonis ML, Dominguez O, Pisano DG, Blasco MA. Identification of TERRA locus unveils a telomere protection role through association to nearly all chromosomes. Nat Commun. 2014;5:4723. doi: 10.1038/ncomms5723 25182072; PubMed Central PMCID: PMC4164772.

22. Deng Z, Norseen J, Wiedmer A, Riethman H, Lieberman PM. TERRA RNA binding to TRF2 facilitates heterochromatin formation and ORC recruitment at telomeres. Mol Cell. 2009;35(4):403–13. doi: 10.1016/j.molcel.2009.06.025 19716786; PubMed Central PMCID: PMC2749977.

23. Graf M, Bonetti D, Lockhart A, Serhal K, Kellner V, Maicher A, et al. Telomere Length Determines TERRA and R-Loop Regulation through the Cell Cycle. Cell. 2017;170(1):72–85 e14. doi: 10.1016/j.cell.2017.06.006 28666126.

24. Flynn RL, Cox KE, Jeitany M, Wakimoto H, Bryll AR, Ganem NJ, et al. Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors. Science. 2015;347(6219):273–7. doi: 10.1126/science.1257216 25593184; PubMed Central PMCID: PMC4358324.

25. Sampl S, Pramhas S, Stern C, Preusser M, Marosi C, Holzmann K. Expression of telomeres in astrocytoma WHO grade 2 to 4: TERRA level correlates with telomere length, telomerase activity, and advanced clinical grade. Transl Oncol. 2012;5(1):56–65. doi: 10.1593/tlo.11202 22348177; PubMed Central PMCID: PMC3281409.

26. Porro A, Feuerhahn S, Reichenbach P, Lingner J. Molecular dissection of telomeric repeat-containing RNA biogenesis unveils the presence of distinct and multiple regulatory pathways. Mol Cell Biol. 2010;30(20):4808–17. doi: 10.1128/MCB.00460-10 20713443; PubMed Central PMCID: PMC2950545.

27. Cusanelli E, Chartrand P. Telomeric repeat-containing RNA TERRA: a noncoding RNA connecting telomere biology to genome integrity. Front Genet. 2015;6:143. doi: 10.3389/fgene.2015.00143 25926849; PubMed Central PMCID: PMC4396414.

28. Wang C, Zhao L, Lu S. Role of TERRA in the regulation of telomere length. Int J Biol Sci. 2015;11(3):316–23. doi: 10.7150/ijbs.10528 25678850; PubMed Central PMCID: PMC4323371.

29. Bunger MK, Wilsbacher LD, Moran SM, Clendenin C, Radcliffe LA, Hogenesch JB, et al. Mop3 is an essential component of the master circadian pacemaker in mammals. Cell. 2000;103(7):1009–17. doi: 10.1016/s0092-8674(00)00205-1 11163178; PubMed Central PMCID: PMC3779439.

30. Carlucci M, Krisciunas A, Li H, Gibas P, Koncevicius K, Petronis A, et al. DiscoRhythm: Interactive Workflow for Discovering Rhythmicity in Biological Data. R package version 100. 2019.

31. Raduwan H, Isola AL, Belden WJ. Methylation of histone H3 on lysine 4 by the lysine methyltransferase SET1 protein is needed for normal clock gene expression. J Biol Chem. 2013;288(12):8380–90. Epub 2013/01/16. doi: 10.1074/jbc.M112.359935 23319591; PubMed Central PMCID: PMC3605655.

32. Belden WJ, Loros JJ, Dunlap JC. Execution of the circadian negative feedback loop in Neurospora requires the ATP-dependent chromatin-remodeling enzyme CLOCKSWITCH. Mol Cell. 2007;25(4):587–600. Epub 2007/02/24. doi: 10.1016/j.molcel.2007.01.010 17317630.

33. Smith KM, Sancar G, Dekhang R, Sullivan CM, Li S, Tag AG, et al. Transcription factors in light and circadian clock signaling networks revealed by genomewide mapping of direct targets for neurospora white collar complex. Eukaryot Cell. 2010;9(10):1549–56. Epub 2010/08/03. doi: 10.1128/EC.00154-10 20675579; PubMed Central PMCID: PMC2950426.

34. Rey G, Cesbron F, Rougemont J, Reinke H, Brunner M, Naef F. Genome-wide and phase-specific DNA-binding rhythms of BMAL1 control circadian output functions in mouse liver. PLoS Biol. 2011;9(2):e1000595. Epub 2011/03/03. doi: 10.1371/journal.pbio.1000595 21364973; PubMed Central PMCID: PMC3043000.

35. Koike N, Yoo SH, Huang HC, Kumar V, Lee C, Kim TK, et al. Transcriptional architecture and chromatin landscape of the core circadian clock in mammals. Science. 2012;338(6105):349–54. Epub 2012/09/01. doi: 10.1126/science.1226339 22936566; PubMed Central PMCID: PMC3694775.

36. Li H, Durbin R. Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics. 2010;26(5):589–95. Epub 2010/01/19. doi: 10.1093/bioinformatics/btp698 20080505; PubMed Central PMCID: PMC2828108.

37. Robinson JT, Thorvaldsdottir H, Winckler W, Guttman M, Lander ES, Getz G, et al. Integrative genomics viewer. Nat Biotechnol. 2011;29(1):24–6. Epub 2011/01/12. doi: 10.1038/nbt.1754 21221095; PubMed Central PMCID: PMC3346182.

38. Lee HC, Li L, Gu W, Xue Z, Crosthwaite SK, Pertsemlidis A, et al. Diverse pathways generate microRNA-like RNAs and Dicer-independent small interfering RNAs in fungi. Mol Cell. 2010;38(6):803–14. Epub 2010/04/27. doi: 10.1016/j.molcel.2010.04.005 20417140; PubMed Central PMCID: PMC2902691.

39. Wright C, Herbert G, Pilkington R, Callaghan M, McClean S. Real-time PCR method for the quantification of Burkholderia cepacia complex attached to lung epithelial cells and inhibition of that attachment. Lett Appl Microbiol. 2010;50(5):500–6. doi: 10.1111/j.1472-765X.2010.02828.x 20337933.

40. Ripperger JA, Schibler U. Rhythmic CLOCK-BMAL1 binding to multiple E-box motifs drives circadian Dbp transcription and chromatin transitions. Nature genetics. 2006;38(3):369–74. doi: 10.1038/ng1738 16474407.

41. Cao F, Li X, Hiew S, Brady H, Liu Y, Dou Y. Dicer independent small RNAs associate with telomeric heterochromatin. RNA. 2009;15(7):1274–81. doi: 10.1261/rna.1423309 19460867; PubMed Central PMCID: PMC2704082.

42. Pizarro A, Hayer K, Lahens NF, Hogenesch JB. CircaDB: a database of mammalian circadian gene expression profiles. Nucleic Acids Res. 2013;41(Database issue):D1009–13. Epub 2012/11/28. doi: 10.1093/nar/gks1161 23180795; PubMed Central PMCID: PMC3531170.

43. Collado M, Blasco MA, Serrano M. Cellular senescence in cancer and aging. Cell. 2007;130(2):223–33. doi: 10.1016/j.cell.2007.07.003 17662938.

44. Allsopp RC, Vaziri H, Patterson C, Goldstein S, Younglai EV, Futcher AB, et al. Telomere length predicts replicative capacity of human fibroblasts. Proc Natl Acad Sci U S A. 1992;89(21):10114–8. Epub 1992/11/01. doi: 10.1073/pnas.89.21.10114 1438199; PubMed Central PMCID: PMC50288.

45. Li N, Joska TM, Ruesch CE, Coster SJ, Belden WJ. The frequency natural antisense transcript first promotes, then represses, frequency gene expression via facultative heterochromatin. Proc Natl Acad Sci U S A. 2015;112(14):4357–62. doi: 10.1073/pnas.1406130112 25831497; PubMed Central PMCID: PMC4394252.

46. Belden WJ, Lewis ZA, Selker EU, Loros JJ, Dunlap JC. CHD1 remodels chromatin and influences transient DNA methylation at the clock gene frequency. PLoS Genet. 2011;7(7):e1002166. Epub 2011/08/04. doi: 10.1371/journal.pgen.1002166 21811413; PubMed Central PMCID: PMC3140994.

47. Bernard P, Allshire R. Centromeres become unstuck without heterochromatin. Trends Cell Biol. 2002;12(9):419–24. Epub 2002/09/11. 12220862.

48. Tu S, Yuan GC, Shao Z. The PRC2-binding long non-coding RNAs in human and mouse genomes are associated with predictive sequence features. Sci Rep. 2017;7:41669. Epub 2017/02/01. doi: 10.1038/srep41669 28139710; PubMed Central PMCID: PMC5282597.

49. Ruger M, Scheer FA. Effects of circadian disruption on the cardiometabolic system. Rev Endocr Metab Disord. 2009;10(4):245–60. doi: 10.1007/s11154-009-9122-8 19784781; PubMed Central PMCID: PMC3026852.

50. Kondratov RV, Kondratova AA, Gorbacheva VY, Vykhovanets OV, Antoch MP. Early aging and age-related pathologies in mice deficient in BMAL1, the core componentof the circadian clock. Genes Dev. 2006;20(14):1868–73. Epub 2006/07/19. 20/14/1868 [pii] doi: 10.1101/gad.1432206 16847346; PubMed Central PMCID: PMC1522083.

51. Bunger MK, Walisser JA, Sullivan R, Manley PA, Moran SM, Kalscheur VL, et al. Progressive arthropathy in mice with a targeted disruption of the Mop3/Bmal-1 locus. Genesis. 2005;41(3):122–32. doi: 10.1002/gene.20102 15739187.

52. McDearmon EL, Patel KN, Ko CH, Walisser JA, Schook AC, Chong JL, et al. Dissecting the functions of the mammalian clock protein BMAL1 by tissue-specific rescue in mice. Science. 2006;314(5803):1304–8. doi: 10.1126/science.1132430 17124323; PubMed Central PMCID: PMC3756687.

53. Jenwitheesuk A, Nopparat C, Mukda S, Wongchitrat P, Govitrapong P. Melatonin regulates aging and neurodegeneration through energy metabolism, epigenetics, autophagy and circadian rhythm pathways. Int J Mol Sci. 2014;15(9):16848–84. doi: 10.3390/ijms150916848 25247581; PubMed Central PMCID: PMC4200827.

54. Qu Y, Mao M, Li X, Liu Y, Ding J, Jiang Z, et al. Telomerase reconstitution contributes to resetting of circadian rhythm in fibroblasts. Mol Cell Biochem. 2008;313(1–2):11–8. doi: 10.1007/s11010-008-9736-2 18398672.

55. Chen WD, Wen MS, Shie SS, Lo YL, Wo HT, Wang CC, et al. The circadian rhythm controls telomeres and telomerase activity. Biochem Biophys Res Commun. 2014;451(3):408–14. doi: 10.1016/j.bbrc.2014.07.138 25109806.

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2019 Číslo 10
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