Distinctive DNA sequence features define epigenetic longevity of inflammatory memory

Tissues harbor 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. We show that in mice, epidermal stem cells store lifelong, functional epigenetic records of psoriasis-like skin flares. Applying deep learning to investigate these chromatin dynamics, we unearth CpG dinucleotide density as a major driver of memory persistence. Although unnecessary for inflammation-induced transcription factors to open and establish memories, CpG-enriched sequences thereafter become essential, reinforcing accessibility across cellular generations by integrating DNA demethylation, methylation-sensitive transcription factors, sequence-intrinsic nucleosome disaffinity, and the nucleosome-destabilizing histone variant H2A.Z. Thus, once activated by inflammation-induced transcription factors, DNA sequences orchestrate persistent poise, imparting long-lasting memory to stress-sensitive genes and profoundly affecting tissue fitness upon recall.