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