Epigenetic inheritance and boundary maintenance at human centromeres

Centromeres are chromosomal regions that provide the foundation for microtubule attachment during chromosome segregation. Centromeres are epigenetically defined by nucleosomes containing the histone H3 variant centromere protein A (CENP-A) and, in many organisms, are surrounded by transcriptionally repressed pericentromeric chromatin marked by trimethylation of histone H3 lysine 9 (H3K9me3). Pericentromeric regions facilitate sister chromatid cohesion during mitosis, thereby supporting centromere function. Heterochromatin has a known propensity to spread into adjacent euchromatic domains unless it is properly bounded. Heterochromatin spreading into the centromere can disrupt kinetochore function, perturbing chromosome segregation and genome stability. In the fission yeast Schizosaccharomyces pombe, tRNA genes provide barriers to heterochromatin spread at the centromere, the absence of which results in abnormal meiotic chromosome segregation. How heterochromatin-centromere boundaries are established in humans is not understood. We propose models for stable epigenetic inheritance of centromeric domains in humans and discuss advances that will enable the discovery of novel regulators of this process.