Single-nucleus transcriptomics uncovers a geroprotective role of YAP in primate gingival aging

  • Qinchao Hu 1,2 ,
  • Bin Zhang 1,7,8 ,
  • Yaobin Jing 1,7,9,10,13 ,
  • Shuai Ma 1,7,9,10,14 ,
  • Lei Hu 3 ,
  • Jingyi Li 1,7,8,9,10,14 ,
  • Yandong Zheng 6,7,8 ,
  • Zijuan Xin 1,7,9,10 ,
  • Jianmin Peng 2 ,
  • Si Wang 11,12,14 ,
  • Bin Cheng 2 ,
  • Jing Qu , 6,7,8,9,10,14 ,
  • Weiqi Zhang , 5,8,9,14 ,
  • Guang-Hui Liu , 1,7,8,9,10,11,12,14 ,
  • Songlin Wang , 3,4
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  • 1. State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
  • 2. Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou 510060, China
  • 3. Salivary Gland Disease Center and Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Beijing Laboratory of Oral Health and Beijing Stomatological Hospital, Capital Medical University, Beijing 100050, China
  • 4. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
  • 5. CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing 100101, China
  • 6. State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
  • 7. Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
  • 8. University of Chinese Academy of Sciences, Beijing 100049, China
  • 9. Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
  • 10. Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
  • 11. Advanced Innovation Center for Human Brain Protection and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China
  • 12. Aging Translational Medicine Center, International Center for Aging and Cancer, Beijing Municipal Geriatric Medical Research Center, Xuan Wu Hospital, Capital Medical University, Beijing 100053, China
  • 13. International Center for Aging and Cancer, Hainan Medical University, Haikou 571199, China
  • 14. Aging Biomarker Consortium, Beijing 100101, China
qujing@ioz.ac.cn
zhangwq@big.ac.cn
ghliu@ioz.ac.cn
slwang@ccmu.edu.cn

Received date: 09 Dec 2023

Accepted date: 01 Feb 2024

Copyright

2024 The Author(s) 2024. Published by Oxford University Press on behalf of Higher Education Press.

Abstract

Aging has a profound impact on the gingiva and significantly increases its susceptibility to periodontitis, a worldwide prevalent inflammatory disease. However, a systematic characterization and comprehensive understanding of the regulatory mechanism underlying gingival aging is still lacking. Here, we systematically dissected the phenotypic characteristics of gingiva during aging in primates and constructed the first single-nucleus transcriptomic landscape of gingival aging, by which a panel of cell type-specific signatures were elucidated. Epithelial cells were identified as the most affected cell types by aging in the gingiva. Further analyses pinpointed the crucial role of YAP in epithelial self-renew and homeostasis, which declined during aging in epithelial cells, especially in basal cells. The decline of YAP activity during aging was confirmed in the human gingival tissues, and downregulation of YAP in human primary gingival keratinocytes recapitulated the major phenotypic defects observed in the aged primate gingiva while overexpression of YAP showed rejuvenation effects. Our work provides an in-depth understanding of gingival aging and serves as a rich resource for developing novel strategies to combat aging-associated gingival diseases, with the ultimate goal of advancing periodontal health and promoting healthy aging.

Cite this article

Qinchao Hu , Bin Zhang , Yaobin Jing , Shuai Ma , Lei Hu , Jingyi Li , Yandong Zheng , Zijuan Xin , Jianmin Peng , Si Wang , Bin Cheng , Jing Qu , Weiqi Zhang , Guang-Hui Liu , Songlin Wang . Single-nucleus transcriptomics uncovers a geroprotective role of YAP in primate gingival aging[J]. Protein & Cell, 2024 , 15(8) : 612 -632 . DOI: 10.1093/procel/pwae017

1
Aging Biomarker C, Bao H, Cao J et al. Biomarkers of aging. Sci China Life Sci 2023;66:893–1066.

DOI

2
Aibar S, González-Blas CB, Moerman T et al. SCENIC: single- cell regulatory network inference and clustering. Nat Methods 2017;14:1083–1086.

DOI

3
Anerillas C, Mazan-Mamczarz K, Herman AB et al. The YAP-TEAD complex promotes senescent cell survival by lowering endoplasmic reticulum stress. Nat Aging 2023;3:1237–1250.

DOI

4
Bartold PM, Walsh LJ, Narayanan AS. Molecular and cell biology of the gingiva. Periodontol 2000 2000;24:28–55.

DOI

5
Butler A, Hoffman P, Smibert P et al. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat Biotechnol 2018;36:411–420.

DOI

6
Caetano AJ, Yianni V, Volponi A et al. Defining human mesenchymal and epithelial heterogeneity in response to oral inflammatory disease. eLife 2021;10:e62810.

DOI

7
Cai Y, Song W, Li J et al. The landscape of aging. Sci China Life Sci 2022;65:2354–2454.

DOI

8
Calenic B, Greabu M, Caruntu C et al. Oral keratinocyte stem/progenitor cells: specific markers, molecular signaling pathways and potential uses. Periodontol 2000 2015;69:68–82.

DOI

9
Chen S, Zhou D, Liu O et al. Cellular senescence and periodontitis: mechanisms and therapeutics. Biology (Basel) 2022;11:1419.

DOI

10
Cordenonsi M, Zanconato F, Azzolin L et al. The Hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells. Cell 2011;147:759–772.

DOI

11
Dobin A, Davis CA, Schlesinger F et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 2013;29:15–21.

DOI

12
Driskill JH, Pan D. Control of stem cell renewal and fate by YAP and TAZ. Nat Rev Mol Cell Biol 2023;24:895–911.

DOI

13
Dutzan N, Abusleme L, Bridgeman H et al. On-going mechanical damage from mastication drives homeostatic Th17 Cell responses at the oral barrier. Immunity 2017;46:133–147.

DOI

14
Ebersole JL, Gonzalez OA. Mucosal circadian rhythm pathway genes altered by aging and periodontitis. PLoS One 2022;17:e0275199.

DOI

15
Efremova M, Vento-Tormo M, Teichmann SA et al. CellPhoneDB: inferring cell-cell communication from combined expression of multi-subunit ligand-receptor complexes. Nat Protoc 2020;15:1484–1506.

DOI

16
Eke PI, Wei L, Borgnakke WS et al. Periodontitis prevalence in adults >/= 65 years of age, in the USA. Periodontol 2000 2016;72:76–95.

DOI

17
Eskan MA, Jotwani R, Abe T et al. The leukocyte integrin antagonist Del-1 inhibits IL-17-mediated inflammatory bone loss. Nat Immunol 2012;13:465–473.

DOI

18
Fleming SJ, Chaffin MD, Arduini A et al. Unsupervised removal of systematic background noise from droplet-based single-cell experiments using CellBender. Nat Methods 2023;20:1323–1335.

DOI

19
Fu L, Hu Y, Song M et al. Up-regulation of FOXD1 by YAP alleviates senescence and osteoarthritis. PLoS Biol 2019;17:e3000201.

DOI

20
Fu M, Hu Y, Lan T et al. The Hippo signalling pathway and its implications in human health and diseases. Signal Transduct Target Ther 2022;7:376.

DOI

21
Gonzalez OA, Stromberg AJ, Huggins PM et al. Apoptotic genes are differentially expressed in aged gingival tissue. J Dent Res 2011;90:880–886.

DOI

22
Gonzalez OA, Novak MJ, Kirakodu S et al. Comparative analysis of gingival tissue antigen presentation pathways in ageing and periodontitis. J Clin Periodontol 2014;41:327–339.

DOI

23
Groeger S, Meyle J. Oral mucosal epithelial cells. Front Immunol 2019;10:208.

DOI

24
Hajishengallis G, Chavakis T. Local and systemic mechanisms linking periodontal disease and inflammatory comorbidities. Nat Rev Immunol 2021;21:426–440.

DOI

25
Hlusko LJ, Schmitt CA, Monson TA et al. The integration of quantitative genetics, paleontology, and neontology reveals genetic underpinnings of primate dental evolution. Proc Natl Acad Sci U S A 2016;113:9262–9267.

DOI

26
Huang D, Zuo Y, Zhang C et al. A single-nucleus transcriptomic atlas of primate testicular aging reveals exhaustion of the spermatogonial stem cell reservoir and loss of Sertoli cell homeostasis. Protein Cell 2023;14:888–907.

DOI

27
Jing Y, Zuo Y, Yu Y et al. Single-nucleus profiling unveils a geroprotective role of the FOXO3 in primate skeletal muscle aging. Protein Cell 2023;14:497–512.

DOI

28
Kinane DF, Stathopoulou PG, Papapanou PN. Periodontal diseases. Nat Rev Dis Primers 2017;3:17038.

DOI

29
Krishnaswami SR, Grindberg RV, Novotny M et al. Using single nuclei for RNA-seq to capture the transcriptome of postmortem neurons. Nat Protoc 2016;11:499–524.

DOI

30
Lamster IB, Asadourian L, Del Carmen T et al. The aging mouth: differentiating normal aging from disease. Periodontol 2000 2016;72:96–107.

DOI

31
Li J, Zheng Y, Yan P et al. A single-cell transcriptomic atlas of primate pancreatic islet aging. Natl Sci Rev 2021;8:nwaa127.

DOI

32
Liao Y, Smyth GK, Shi W. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics 2014;30:923–930.

DOI

33
Liberzon A, Birger C, Thorvaldsdottir H et al. The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst 2015;1:417–425.

DOI

34
Liu N, Matsumura H, Kato T et al. Stem cell competition orchestrates skin homeostasis and ageing. Nature 2019;568:344–350.

DOI

35
Liu X, Liu Z, Wu Z et al. Resurrection of endogenous retroviruses during aging reinforces senescence. Cell 2023;186:287–304.e26.

DOI

36
Lou MM, Tang XQ, Wang GM et al. Long noncoding RNA BS-DRL1 modulates the DNA damage response and genome stability by interacting with HMGB1 in neurons. Nat Commun 2021;12:4075.

DOI

37
Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 2014;15:550.

DOI

38
Ma S, Sun S, Geng L et al. Caloric Restriction Reprograms the Single-Cell Transcriptional Landscape of Rattus Norvegicus Aging. Cell 2020;180:984–1001.e22.

DOI

39
Ma S, Sun S, Li J et al. Single-cell transcriptomic atlas of primate cardiopulmonary aging. Cell Res 2021;31:415–432.

DOI

40
Ma S, Chi X, Cai Y et al. Decoding aging hallmarks at the single- cell level. Annu Rev Biomed Data Sci 2023;6:129–152.

DOI

41
McGinnis CS, Murrow LM, Gartner ZJ. DoubletFinder: doublet detection in single-cell RNA sequencing data using artificial nearest neighbors. Cell Systems 2019;8:329–337.e4.

DOI

42
Moutsopoulos NM, Konkel JE. Tissue-specific immunity at the oral mucosal barrier. Trends Immunol 2018;39:276–287.

DOI

43
Moya IM, Halder G. Hippo-YAP/TAZ signalling in organ regeneration and regenerative medicine. Nat Rev Mol Cell Biol 2019;20:211–226.

DOI

44
Pan X, Wu B, Fan X et al. YAP accelerates vascular senescence via blocking autophagic flux and activating mTOR. J Cell Mol Med 2021;25:170–183.

DOI

45
Panciera T, Azzolin L, Cordenonsi M et al. Mechanobiology of YAP and TAZ in physiology and disease. Nat Rev Mol Cell Biol 2017;18:758–770.

DOI

46
Pandruvada SN, Gonzalez OA, Kirakodu S et al. Bone biology- related gingival transcriptome in ageing and periodontitis in non-human primates. J Clin Periodontol 2016;43:408–417.

DOI

47
Pinero J, Bravo A, Queralt-Rosinach N et al. DisGeNET: a comprehensive platform integrating information on human disease-associated genes and variants. Nucleic Acids Res 2017;45:D833–D839.

DOI

48
Pinero J, Ramirez-Anguita JM, Sauch-Pitarch J et al. The DisGeNET knowledge platform for disease genomics: 2019 update. Nucleic Acids Res 2020;48:D845–D855.

DOI

49
Qian S-j, Huang Q-r, Chen R-y et al. Single-Cell RNA sequencing identifies new inflammation-promoting cell subsets in Asian patients with chronic periodontitis. Front Immunol 2021;12:711337.

DOI

50
Qiu X, Hill A, Packer J et al. Single-cell mRNA quantification and differential analysis with Census. Nat Methods 2017;14:309–315.

DOI

51
Romandini M, Baima G, Antonoglou G et al. Periodontitis, edentulism, and risk of mortality: a systematic review with meta-analyses. J Dent Res 2021;100:37–49.

DOI

52
Roth GS, Mattison JA, Ottinger MA et al. Aging in rhesus monkeys: relevance to human health interventions. Science 2004;305:1423–1426.

DOI

53
Silva LM, Doyle AD, Greenwell-Wild T et al. Fibrin is a critical regulator of neutrophil effector function at the oral mucosal barrier. Science 2021;374:eabl5450.

DOI

54
Skinnider MA, Squair JW, Kathe C et al. Cell type prioritization in single-cell data. Nat Biotechnol 2021;39:30–34.

DOI

55
Sladitschek-Martens HL, Guarnieri A, Brumana G et al. YAP/TAZ activity in stromal cells prevents ageing by controlling cGAS-STING. Nature 2022;607:790–798.

DOI

56
Sun SC. Non-canonical NF-kappaB signaling pathway. Cell Res 2011;21:71–85.

DOI

57
Vitkov L, Singh J, Schauer C et al. Breaking the gingival barrier in periodontitis. Int J Mol Sci 2023;24:4544.

DOI

58
Wang VY, Li Y, Kim D et al. Bcl3 phosphorylation by Akt, Erk2, and IKK is required for its transcriptional activity. Mol Cell 2017;67:484–497.e5.

DOI

59
Wang Y, Xu X, Maglic D et al. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of the Hippo Signaling Pathway in cancer. Cell Rep 2018;25:1304–1317.e5.

60
Wang S, Zheng Y, Li J et al. Single-cell transcriptomic Atlas of primate ovarian aging. Cell 2020;180:585–600.e19.

DOI

61
Wang S, Zheng Y, Li Q et al. Deciphering primate retinal aging at single-cell resolution. Protein Cell 2021;12:889–898.

DOI

62
Wang K, Liu H, Hu Q et al. Epigenetic regulation of aging: implications for interventions of aging and diseases. Signal Transduct Target Ther 2022;7:374.

DOI

63
Wang C, Yang K, Liu X et al. MAVS antagonizes human stem cell senescence as a mitochondrial stabilizer. Research 2023a;6:0192.

DOI

64
Wang J, Lu X, Zhang W et al. Endogenous retroviruses in development and health. Trends Microbiol 2023b;32:342–354.

DOI

65
Wickham H. ggplot2: Elegant Graphics for Data Analysis. New York: Springer-Verlag, 2016.

DOI

66
Williams DW, Greenwell-Wild T, Brenchley L et al. Human oral mucosa cell atlas reveals a stromal-neutrophil axis regulating tissue immunity. Cell 2021;184:4090–4104 e4015.

DOI

67
Wu Z, Qu J, Zhang W et al. Stress, epigenetics, and aging: unraveling the intricate crosstalk. Mol Cell 2023;84:34–54.

DOI

68
Yang S, Liu C, Jiang M et al. A single-nucleus transcriptomic atlas of primate liver aging uncovers the pro-senescence role of SREBP2 in hepatocytes. Protein Cell 2023;15:98–120.

DOI

69
Yuan Y, Park J, Feng A et al. YAP1/TAZ-TEAD transcriptional networks maintain skin homeostasis by regulating cell proliferation and limiting KLF4 activity. Nat Commun 2020;11:1472.

DOI

70
Zang Y, Song JH, Oh SH et al. Targeting NLRP3 inflammasome reduces age-related experimental alveolar bone loss. J Dent Res 2020;99:1287–1295.

DOI

71
Zhang W, Qu J, Liu GH et al. The ageing epigenome and its rejuvenation. Nat Rev Mol Cell Biol 2020a;21:137–150.

DOI

72
Zhang W, Zhang S, Yan P et al. A single-cell transcriptomic landscape of primate arterial aging. Nat Commun 2020b;11:2202.

DOI

73
Zhang H, Li J, Ren J et al. Single-nucleus transcriptomic landscape of primate hippocampal aging. Protein Cell 2021;12:695–716.

DOI

74
Zhang H, Li J, Yu Y et al. Nuclear lamina erosion-induced resurrection of endogenous retroviruses underlies neuronal aging. Cell Rep 2023a;42:112593.

DOI

75
Zhang Y, Zheng Y, Wang S et al. Single-nucleus transcriptomics reveals a gatekeeper role for FOXP1 in primate cardiac aging. Protein Cell 2023b;14:279–293.

DOI

76
Zhou Y, Zhou B, Pache L et al. Metascape provides a biologist- oriented resource for the analysis of systemslevel datasets. Nat Commun 2019;10:1523.

DOI

77
Zou S, Tong Q, Liu B et al. Targeting STAT3 in cancer immunotherapy. Mol Cancer 2020;19:145.

DOI

78
Zou Z, Long X, Zhao Q et al. A single-cell transcriptomic Atlas of human skin aging. Dev Cell 2021;56:383–397.e8.

DOI

79
Zucchelli G, Mounssif I. Periodontal plastic surgery. Periodontol 2000 2015;68:333–368.

DOI

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