Unique sequence features define epigenetic longevity of inflammatory memory [CUT&Run]

Many tissues harbor epigenetic memories of inflammation, which heighten sensitivity to diverse future assaults. Whether and how these adaptations are sustained through time and cell division remain poorly understood. Here, we show that epidermal stem cells store functional epigenetic records of a psoriatic skin flare that last a lifetime. Applying deep learning to interrogate these chromatin dynamics, we unearth CpG dinucleotide density as a major driver of memory persistence. Molecularly, while unnecessary for stress-induced chromatin opening, CpG dinucleotides thereafter become essential, reinforcing accessibility across cellular generations through a signature integrating DNA demethylation, methylation-sensitive transcription factors, sequence-intrinsic nucleosome disaffinity and nucleosome-destabilizing histone variant H2A.Z. Thus, inherent CpG enrichment within DNA sequence confers enduring adaptability to environmentally sensitive cis-regulatory elements, with profound consequences to long-term tissue fitness.