Interferon stimulation creates chromatin marks and establishes transcriptional memory

Epigenetic memory for experience-based gene expression has not been well studied in higher organisms. Here we demonstrate that cells previously exposed to interferons exhibit a memory response and mount faster and higher transcription upon restimulation in fibroblasts and macrophages. Genome-wide analysis showed that memory was ascribed to accelerated recruitment of transcription factors to the genes. This process rested upon a distinct chromatin state involving the histone H3.3 and H3K36 modification. Our findings provide a mechanistic framework for the previously proposed idea of "trained innate immunity" representing memory, independent of adaptive immunity. Together, this study highlights learning as a fundamental faculty of mammalian somatic cells.