Discovering the epigenetic principles of human centromere seeding and inheritance

Chromosome segregation in mitosis and meiosis ensures the faithful deposition of the genetic complement to daughter cells. This process requires the centromere, a specialized chromosomal locus bound by proteins that tether chromosomes to spindle microtubules. Despite centromeres being discovered over 100 years ago, how one and only one centromere is specified on each chromosome and how these structures are replicated every cell division is a fundamental question in biology and the focus of this proposal. Centromere position and function are critically dependent on a unique chromatin domain featuring the histone H3 variant, Centromere Protein A (CENP-A). Here we ask how can centromeres be seeded by de novo assembly of CENP-A chromatin, how is a stable CENP-A chromatin domain established and how is it inherited. The Jansen and Gruszka labs join forces with highly complementary in vivo and in vitro approaches to discover the components and principles of CENP-A chromatin seeding and maintenance that form the basis of the epigenetic inheritance of human centromeres. This knowledge is crucial to understanding failures in cell division that generate aneuploidy e.g. during oncogenic transformation as well as facilitating future efforts to engineer and build human artificial chromosomes.