Fig. 3

Epigenetic Mechanisms Underlying Stress Resilience to Neuropsychiatric Disorders. Stress increases levels of circulating cortisol that easily passes the cellular membrane. In the cellular plasma, [1] GR forms a complex with chaperones [2] Hsp70 (that partially unfolds and inactivates GR) and [3] Hsp90 (that facilitates GR maturation) [84, 87]. [4] Binding with co-chaperone FKBP51 (encoded by gene fkbp5) inhibits GR capacity for nuclear transactivation/signalling and detaches Hsp70 [35, 48, 99, 100]. [5] Encoded by gene fkbp4, co-chaperone FKBP52 competes with FKBP51 and its replacement increases affinity of the GR-Hsp90 complex to bind cortisol [84, 97]. [6] When cortisol binds, chaperone complex releases and thus GR and HSF1 translocate to the nucleus to initiate transcription linked to [7] memory formation [84, 87, 95, 101] and [8] gene expression for chaperones and co-chaperones that promote GR activation in stress-response [86, 94]. [9] In an ultra-short feedback loop, it also promotes gene fkbp5, which has close proximity to GRE. Polymorphism of fkbp5 is associated with interindividual differences in stress reactivity. In addition, fkbp5 expression increases with age due to decreased DNA methylation. This simplified model does not depict all protein/regulators involved in chaperone machinery and signalling pathways. CREB, cAMP response element-binding protein; GR, glucocorticoid receptor; GRE, glucocorticoid response elements; H, histone; HSF, heat shock factor 1