Assembly and epigenetic inheritance of human centromeres

The centromere is a specialized chromatin domain that drives accurate chromosome segregation. Remarkably, centromere identity is maintained epigenetically and is largely independent of the underlying DNA sequence. We aim to uncover the mechanisms by which chromatin–based information is inherited, using the centromere as a model system. Using fluorescent pulse-labeling approaches, we discovered that the centromeric histone H3 variant CENP-A forms an exceptionally stable chromatin structure that is unique to this histone, consistent with its role in conferring epigenetic identity to the centromere. The replenishment of new CENP-A is tightly coupled to the cell cycle, ensuring synchrony between cell division and centromere propagation. The strong epigenetic nature of centromeres is illustrated by the existence of neocentromeres, which arise spontaneously but are inherited indefinitely. We have developed novel methods to induce neocentromere formation, enabling us to investigate how centromeres are established, how their size and copy number are controlled, and how they are inherited with remarkable fidelity.