Super enhancers, regulatory archipelagos and enhanceropathies

In this fourth and final lecture, Pr Denis Duboule describes the different types of integratedenhancer landscapes, containing either enhancers with identical specificities, or enhancers with complementary specificities, or super-enhancers whose activities add up to maximum transcriptional stimulation of particular target genes. The molecular basis of enhancer function is then briefly outlined, from the arrival of chromatin-opening pioneer factors, through the formation of a spatial loop, to the initiation of target gene transcription. A study is then presented of the evolution of enhancer and promoter sequences in twenty different mammalian species, highlighting essential differences in the evolutionary origin and function of these two types of sequences. Finally, the lecture ends with a description of several types of problems linked either to the malfunctioning of enhancers, or to their absence or topological displacement following chromosomal rearrangements. These different pathological situations are illustrated by numerous human genetic syndromes, showing how the way genes are regulated during our development and everyday life is at least as important as the integrity of the genes themselves.