Global chromatin reorganization and regulation of genes of specific evolutionary age in differentiation and cancer.

Oncogenesis is accompanied by chromatin organization alterations and reactivation of unicellular phenotypes at the metabolic and transcriptional level. The mechanisms connecting these two observations are unexplored, despite its relevance in cancer biology. Assigning evolutionary ages to genes in the context of 3D chromatin structure, we characterize the epigenomic landscape, expression regulation and spatial organization of genes according to their evolutionary ages. We describe topological changes across differentiation and find some of the patterns, involving Polycomb repression and RNA Pol II pausing, being reversed during oncogenesis. Going beyond the evidence of non-random organization of genes and chromatin features in the 3D epigenome, we suggest that these patterns lead to preferential interactions of old, intermediate and young genes, mediated by respectively RNA Polymerase II, Polycomb and the lamina. Our results are in line and expand recent findings implicating loss of Polycomb repression and activation of embryonal and early evolutionary programs in cancer.