Century-old chromatin architecture preserved with formaldehyde

Co-ordinated regulation or dysregulation of chromatin architecture underpins fundamental biological processes, such as embryonic development, disease, cellular programming and response to environmental stress. The dynamic and plastic nature of chromatin accessibility is a major driver of phenotypic diversity, but we know shockingly little about the temporal dynamics of chromatin reorganisation and almost nothing prior to the existence of flash-frozen specimens. Linking two disparate fields by their common use and application of the preservative formaldehyde, we present an approach to characterise chromatin architecture in formaldehyde-preserved specimens up to 117 years old. We characterise how over-fixation modulates but does not eliminate genome-wide patterns of differential chromatin accessibility. Our novel analytical approach identifies promoter regions enriched for gene ontology terms matching the tissue of origin, resulting in sex-specific and environment-dependent genome-wide profiles. Contrary to prevailing dogma, we show that over-fixation is essential for the successful recovery of historical chromatin architecture. Our methodological and analytical advances open the door to the first detailed and comprehensive view of the epigenetic past and reveal a new role for museum collections in understanding chromatin architecture dynamics over the last century.