Epigenetic modifications in thymic epithelial cells: an evolutionary perspective for thymus atrophy

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.

Keywords: EMT; Epigenetic modification; Foxn1; Rejuvenation; Thymic epithelial cell; Thymus atrophy.

Fig. 1

The features and epigenetic changes of TEC senescence. Cellular senescence is characterized by abnormal cell enlargement, cell cycle arrest (by upregulation of p21 & p16 cell cycle inhibitors), resistance to apoptosis (by upregulation of the BCL-2 family), SASP (by upregulation of cytokines, chemokines, extracellular vesicles), and SAHF, metabolic dysfunction (the positive of SA-β-gal staining). Epigenetic changes include DNA methylation, histone modifications and chromatin remodelling, which together play a fine-tuning role in the development, differentiation, and senescence of TECs. SASP, senescence-associated secretory phenotype; SAHF, senescence-associated heterochromatin foci; SA-β-gal, senescence-associated-β-galactosidase; DD, DNA damage; EV, extracellular vesicles

Fig. 2

Epigenetic molecules that regulate the origin, development, and senescence of TECs. Expression of ΔNp63 and Bmp4 could maintain the stemness of epithelial progenitor cells for self-renewal and replenish the loss of mature TECs. The transcription factor Foxn1 is under multiple epigenetic modifications, which is the master regulator during thymus development. Besides, SIRT6 has been identified as a molecular switch necessary to the mTEC development and differentiation via repressed SpiB activity. Aire exerts the repressive function by enrichment of H3K27me3 to maintain the proper TRA expression. However, Foxn1 expression is reductive with age, resulting in TECs senescence associated with an increase in TAp63, which is consistent with the diminishment of the polycomb repressive complexes 1 (CBX4). Jmjd3 lies at the nexus of inflammation and senescence by demethylating H3K27me3 sites and releasing the repressive polycomb group (PcG) proteins from the promoter sequences of senescence genes, such as p53/p21, cytokines, and chemokines. Ultimately, the thymus undergoes aging. HDAC, histone deacetylase; Sirt6, sirtuin 6; Jmjd3, Jumonji domain-containing protein 3; SASP, senescence-associated secretory phenotype; TF, transcription factor

Fig. 3

Model of thymic epithelial cell mesenchymal transition. Activation of the TGF-β signaling pathway contributes to the upregulation of mesenchymal markers by phosphorylating smad protein, such as N-cadherin, vimentin, and fibronectin, the downregulation of the epithelial markers (E-cadherin). Moreover, histone demethylase Jmjd3 can promote the formation of EMT via suppressing the activity of H3K27me3. The Wnt signaling pathway can hinder the age-related thymic adipogenesis by suppressing PPARγ expression. EMT, epithelial-mesenchymal transition; PPARγ, peroxisome proliferators-activated receptors