Epigenetic reprogramming refers to modifications of the DNA that lead to sustained changes in gene expression and cell physiology, but do not involve permanent genetic changes such as mutations and recombination that, e.g., are essential for adaptive immunity.
Ample evidence demonstrated the importance of chromatin-associated proteins (regulators) that add, remove or recognize various chemical modifications (or marks) to specific sites on chromatin. These marks play a key role in determining whether a gene is on or off. Epigenetic regulators are often referred to as writers (add modifications), erasers (remove modifications) and readers (bind to chromatin).
Epigenetic reprogramming underlies the adaptive characteristics of innate immune cells during trained immunity. Initial activation of gene transcription is accompanied by the acquisition of specific chromatin marks, which are only partially lost after elimination of the stimulus.
The enhanced epigenetic status of the innate immune cells results in a stronger response to secondary stimuli upon rechallenge. In case of immune tolerance, the removal of the stimulus results in the loss of activating marks and gene expression returns to basal levels. Following a second encounter with the stimulus, ‘tolerized’ genes will not regain the relevant marks and will remain silent to stimulation.
Restoration of normal gene expression in maladaptive innate immune memory states through highly selective and specific inhibitors of chromatin-modulating proteins promises to be a powerful strategy for the development of important new medicines.