Unique sequence features define epigenetic longevity of inflammatory memory [Bisulfite-Seq]

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.