Emergence of new enhancers at late DNA replicating regions

Abstract

AbstractUnlike protein-coding regions, enhancers generally evolve rapidly. By examining enhancer turnover across mammalian species and in multiple tissue-types, we uncovered a relationship between the emergence of novel enhancers and genome organization, reflected by DNA replication time. While enhancers are most abundant in euchromatic regions, new enhancers emerged almost twice as often in late compared to early replicating regions, independent of transposable elements. Using a deep learning model, we demonstrate that new enhancers are enriched for mutations that alter transcription factor (TF) binding. Overall recent enhancers often exhibit neutral evolution, eQTL enrichment, and greater tissue specificity than their evolutionarily conserved counterparts. Accordingly, transcription factors that bind to these enhancers, inferred by their binding sequences, are also more recently evolved and more tissue-specific in gene expression. A similar relationship with DNA replication time is observed in multiple cancer types. Somatic mutations in cancer are consistently elevated in enhancers that have undergone turnover compared to those that remain unchanged. These results demonstrate a relationship between DNA replication time and enhancer evolution across diverse time scales, suggesting that these observations may be time-invariant principles of genome evolution.