Genetics, epigenetics and back again: Lessons learned from neocentromeres

The duplication and segregation of the genome during cell division is crucial to maintain cell identity, development of organisms and tissue maintenance. Centromeres are at the basis of accurate chromosome segregation as they define the site of assembly of the kinetochore, a large complex of proteins that attaches to spindle microtubules driving chromosome movement during cell division. Here we summarize nearly 40 years of research focussed on centromere specification and the role of local cis elements in creating a stable centromere. Initial discoveries in budding yeast in the 1980s opened up the field and revealed essential DNA sequence elements that define centromere position and function. Further work in humans discovered a centromeric DNA sequence-specific binding protein and centromeric alpha-satellite DNA was found to have the capacity to seed centromeres de novo. Despite the early indication of genetic elements as drivers of centromere specification, the discovery in the nineties of neocentromeres that form on unrelated DNA sequences, shifted the focus to epigenetic mechanisms. While specific sequence elements appeared non-essential, the histone H3 variant CENP-A was identified as a crucial component in centromere specification. Neocentromeres, occurring naturally or induced experimentally, have become an insightful tool to understand the mechanisms for centromere specification and will be the focus of this review. They have helped to define the strong epigenetic chromatin-based component underlying centromere inheritance but also provide new opportunities to understand the enigmatic, yet crucial role that DNA sequence elements play in centromere function and inheritance.