Epigenetic inheritance and boundary maintenance at human centromeres

Abstract

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.

Figure 1:

Epigenetic organization at centromeric regions. At centromeres, CENP-A peaks correspond with regions of reduced CpG methylation and recently expanded repeats and transposable elements (TEs). While H3K9me2 immediately abuts CENP-A, H3K9me3 is proposed to be high within the centromere, with a noticeable dip in levels towards the border of the CENP-A occupying higher-order-repeat. During mitosis, H3.3S31P is also high at regions bordering CENP-A, although the relative levels and patterns of these epigenetic modifications remain unknown (Created with BioRender.com).

Figure 2:

Models for spatial maintenance of epigenetic information at human centromeres. A) Two models are represented here, 1) a templated model where after replicative dilution, templated but controlled addition of CENP-A and H3K9me3 nucleosomes results in stable epigenetic inheritance of core- and peri-centromeric regions and 2) an exclusion model, where the core- and peri-centromeric domains preclude addition of the H3K9me3 and CENP-A, respectively, thereby maintaining the epigenetic status at the regions. B) A genetic boundary model where a DNA element (gray) protects the core centromere containing CENP-A nucleosomes (orange) and H3 containing nucleosomes (blue) from heterochromatin invasion C) Epigenetic boundary model where an epigenetic transition zone (gray) between core- and peri-centromeric domains maintains heterochromatin boundaries (Created with BioRender.com)