Epigenetic Modifications in Thymic Epithelial Cells: an Evolutionary Perspective for Thymus Atrophy

Overview

Journal Clin Epigenetics

Publisher Biomed Central

Specialty Genetics

Date 2021 Nov 25

PMID 34819170

Citations 8

Authors

Cexun Hu

Keyu Zhang

Feng Jiang

Hui Wang

Qixiang Shao

Affiliations

Soon will be listed here.

Abstract

Background: The thymic microenvironment is mainly comprised of thymic epithelial cells, the cytokines, exosomes, surface molecules, and hormones from the cells, and plays a vital role in the development, differentiation, maturation and homeostasis of T lymphocytes. However, the thymus begins to degenerate as early as the second year of life and continues through aging in human beings, leading to a decreased output of naïve T cells, the limited TCR diversity and an expansion of monoclonal memory T cells in the periphery organs. These alternations will reduce the adaptive immune response to tumors and emerging infectious diseases, such as COVID-19, also it is easier to suffer from autoimmune diseases in older people. In the context of global aging, it is important to investigate and clarify the causes and mechanisms of thymus involution.

Main Body: Epigenetics include histone modification, DNA methylation, non-coding RNA effects, and chromatin remodeling. In this review, we discuss how senescent thymic epithelial cells determine and control age-related thymic atrophy, how this process is altered by epigenetic modification. How the thymus adipose influences the dysfunctions of the thymic epithelial cells, and the prospects of targeting thymic epithelial cells for the treatment of thymus atrophy.

Conclusion: Epigenetic modifications are emerging as key regulators in governing the development and senescence of thymic epithelial cells. It is beneficial to re-establish effective thymopoiesis, identify the potential therapeutic strategy and rejuvenate the immune function in the elderly.

Citing Articles

METTL3 governs thymocyte development and thymic involution by regulating ferroptosis.

Jing H, Song J, Sun J, Su S, Hu J, Zhang H Nat Aging. 2024; 4(12):1813-1827.

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Benefit delayed immunosenescence by regulating CD4T cells: A promising therapeutic target for aging-related diseases.

Xia T, Zhou Y, An J, Cui Z, Zhong X, Cui T Aging Cell. 2024; 23(10):e14317.

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Thymus in Cardiometabolic Impairments and Atherosclerosis: Not a Silent Player?.

Kologrivova I, Naryzhnaya N, Suslova T Biomedicines. 2024; 12(7).

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The effect of modified Qiyuan paste on mice with low immunity and sleep deprivation by regulating GABA nerve and immune system.

Rong M, Jia J, Lin M, He X, Xie Z, Wang N Chin Med. 2024; 19(1):84.

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The Proteostasis of Thymic Stromal Cells in Health and Diseases.

Liu T, Xia S Protein J. 2024; 43(3):447-463.

PMID: 38622349 DOI: 10.1007/s10930-024-10197-x.

References

Mendes-Giannini M, Silva J, da Silva J, Donofrio F, Miranda E, Andreotti P . Interactions of Paracoccidioides brasiliensis with host cells: recent advances. Mycopathologia. 2007; 165(4-5):237-48. DOI: 10.1007/s11046-007-9074-z. View

Bleul C, Corbeaux T, Reuter A, Fisch P, Monting J, Boehm T . Formation of a functional thymus initiated by a postnatal epithelial progenitor cell. Nature. 2006; 441(7096):992-6. DOI: 10.1038/nature04850. View

Burnley P, Rahman M, Wang H, Zhang Z, Sun X, Zhuge Q . Role of the p63-FoxN1 regulatory axis in thymic epithelial cell homeostasis during aging. Cell Death Dis. 2013; 4:e932. PMC: 3847336. DOI: 10.1038/cddis.2013.460. View

Chen P, Zhang H, Sun X, Hu Y, Jiang W, Liu Z . microRNA-449a modulates medullary thymic epithelial cell differentiation. Sci Rep. 2017; 7(1):15915. PMC: 5698406. DOI: 10.1038/s41598-017-16162-2. View

Celona B, Weiner A, Di Felice F, Mancuso F, Cesarini E, Rossi R . Substantial histone reduction modulates genomewide nucleosomal occupancy and global transcriptional output. PLoS Biol. 2011; 9(6):e1001086. PMC: 3125158. DOI: 10.1371/journal.pbio.1001086. View

Karimian A, Ahmadi Y, Yousefi B . Multiple functions of p21 in cell cycle, apoptosis and transcriptional regulation after DNA damage. DNA Repair (Amst). 2016; 42:63-71. DOI: 10.1016/j.dnarep.2016.04.008. View

Tan J, Wang Y, Zhang N, Zhu X . Induction of epithelial to mesenchymal transition (EMT) and inhibition on adipogenesis: Two different sides of the same coin? Feasible roles and mechanisms of transforming growth factor β1 (TGF-β1) in age-related thymic involution. Cell Biol Int. 2016; 40(8):842-6. DOI: 10.1002/cbin.10625. View

Li J, Gordon J, Chen E, Xiao S, Wu L, Zuniga-Pflucker J . NOTCH1 signaling establishes the medullary thymic epithelial cell progenitor pool during mouse fetal development. Development. 2020; 147(12). PMC: 7328004. DOI: 10.1242/dev.178988. View

Wei C, Guo D, Zhang K, Liang G, Li Y, Ma Y . Profiling analysis of 17β-estradiol-regulated lncRNAs in mouse thymic epithelial cells. Physiol Genomics. 2018; 50(8):553-562. DOI: 10.1152/physiolgenomics.00098.2017. View

10.

Rossi S, Kim M, Leibbrandt A, Parnell S, Jenkinson W, Glanville S . RANK signals from CD4(+)3(-) inducer cells regulate development of Aire-expressing epithelial cells in the thymic medulla. J Exp Med. 2007; 204(6):1267-72. PMC: 2118623. DOI: 10.1084/jem.20062497. View

11.

Shanley D, Aw D, Manley N, Palmer D . An evolutionary perspective on the mechanisms of immunosenescence. Trends Immunol. 2009; 30(7):374-81. DOI: 10.1016/j.it.2009.05.001. View

12.

Dong J, Warner L, Lin L, Chen M, OConnell R, Lu L . miR-155 promotes T reg cell development by safeguarding medullary thymic epithelial cell maturation. J Exp Med. 2020; 218(2). PMC: 7608066. DOI: 10.1084/jem.20192423. View

13.

Ramadoss S, Chen X, Wang C . Histone demethylase KDM6B promotes epithelial-mesenchymal transition. J Biol Chem. 2012; 287(53):44508-17. PMC: 3531764. DOI: 10.1074/jbc.M112.424903. View

14.

Liang Z, Zhang L, Su H, Luan R, Na N, Sun L . MTOR signaling is essential for the development of thymic epithelial cells and the induction of central immune tolerance. Autophagy. 2017; 14(3):505-517. PMC: 5915037. DOI: 10.1080/15548627.2017.1376161. View

15.

Zook E, Krishack P, Zhang S, Zeleznik-Le N, Firulli A, Witte P . Overexpression of Foxn1 attenuates age-associated thymic involution and prevents the expansion of peripheral CD4 memory T cells. Blood. 2011; 118(22):5723-31. PMC: 3228493. DOI: 10.1182/blood-2011-03-342097. View

16.

Yuan S, Li F, Meng Q, Zhao Y, Chen L, Zhang H . Post-transcriptional Regulation of Keratinocyte Progenitor Cell Expansion, Differentiation and Hair Follicle Regression by miR-22. PLoS Genet. 2015; 11(5):e1005253. PMC: 4447420. DOI: 10.1371/journal.pgen.1005253. View

17.

Pangrazzi L, Weinberger B . T cells, aging and senescence. Exp Gerontol. 2020; 134:110887. DOI: 10.1016/j.exger.2020.110887. View

18.

Schuddekopf K, Schorpp M, Boehm T . The whn transcription factor encoded by the nude locus contains an evolutionarily conserved and functionally indispensable activation domain. Proc Natl Acad Sci U S A. 1996; 93(18):9661-4. PMC: 38485. DOI: 10.1073/pnas.93.18.9661. View

19.

Zhang Q, Liang Z, Zhang J, Lei T, Dong X, Su H . Regulates the Development of Medullary Thymic Epithelial Cells and Contributes to the Establishment of Central Immune Tolerance. Front Cell Dev Biol. 2021; 9:655552. PMC: 8044826. DOI: 10.3389/fcell.2021.655552. View

20.

Hirayama T, Asano Y, Iida H, Watanabe T, Nakamura T, Goitsuka R . Meis1 is required for the maintenance of postnatal thymic epithelial cells. PLoS One. 2014; 9(3):e89885. PMC: 3942356. DOI: 10.1371/journal.pone.0089885. View