The dynamic centromere

Abstract

Centromeres are fundamental chromosomal structures that ensure accurate chromosome segregation during cell division. Despite their conserved and essential role in maintaining genomic stability, centromeres are subject to rapid evolutionary change. At the heart of centromere identity is the histone H3 variant CENP-A, an epigenetic mark that defines and propagates active centromeres and is essential for their function. Recent evidence supports a rapid evolution of centromere DNA sequences but also suggests a certain degree of flexibility in CENP-A deposition and propagation. The phenomenon of centromere drift, recently observed in humans, highlights how the dynamic repositioning of CENP-A and associated epigenetic environment over time maintains a regulated equilibrium, ensuring centromere function despite positional variation. Understanding these processes is crucial for unraveling centromere dynamics and their broader implications for genome stability and evolution.

Keywords: CENP-A; Centromeres; Chromatin; Epigenetics; Evolution; Mitosis.

Fig. 1

Comparative organization of centromeres across species. (A) Centromere organization in Saccharomyces cerevisiae (budding yeast). The centromere consists of a ~ 125 bp DNA region divided into three conserved elements: CDE I (~ 8–10 bp, AT-rich), CDE II (~ 78–86 bp, AT-rich), and CDE III (~ 26 bp, highly conserved region). The CDE II region serves as the primary site for CENP-A (Cse4) nucleosome deposition. (B) Schematic representation of the centromere structure in Schizosaccharomyces pombe (fission yeast), highlighting the arrangement of distinct repeat elements and the central core region. Each centromere consists of an inner core region (imr) flanked by outer repeat elements (dg and dh), which are essential for heterochromatin formation. The central core (cc) is the site of CENP-A (Cnp1) nucleosome deposition. (C) Centromere organization in C. elegans. The panel illustrates a chromosome with dispersed centromeric regions (red bands) along its length, reflecting the holocentric nature of C. elegans chromosomes. Tables show the underlying DNA composition and epigenetic landscape of centromeric chromatin versus intercentromeric chromatin. Centromeric chromatin is enriched for the histone variant CENP-A (HCP-3). (D) Schematic representation of a Drosophila centromere composed of a central CENP-A (CID) enriched island (101–171 kb in length), flanked by large blocks of simple satellite DNA (light gray and blue chevrons) that make up the surrounding pericentromeric heterochromatin. The island contains complex DNA sequences, including G2/Jockey-3 non-LTR retrotransposable elements (yellow rectangles), which are interspersed throughout the region. While each centromere has a unique sequence composition, the overall structure of satellite-rich flanks and a retroelement-enriched core is conserved across chromosomes. (E) Left panel: The centromere of a chicken macrochromosome, which consists of chromosome-specific, homogeneous tandem repetitive arrays spanning several hundred kilobases. The arrangement of these sequences varies among centromeres, with different lengths and homology regions. Below these centromere sequences, CENP-A deposition is shown in red, indicating the establishment of a functional centromere. Right panel: The centromere of a chicken microchromosome consisting of non-tandem repetitive sequences. Despite the absence of extensive tandem repeats, these centromeres remain functional, as indicated by CENP-A deposition (red) below the region. (F) Representation of human centromere organization. Human centromeres are composed of α-satellite DNA, which includes monomeric repeat units further organized into higher order repeat (HOR) structures that form chromosome specific arrays. The schematic illustrates the clustering of CENP-A (red) within the active HOR, marking the location of the functional active centromere. (G) Evolutionary layering expansion of centromeric α-satellite DNA. Older, more divergent HOR arrays are concentrated at the periphery of the centromere (yellow and orange chevrons), representing ancestral repeat units. In contrast, newer and evolutionary younger, more homogeneous HORs are expanding at the center, reflecting ongoing centromeric sequence evolution and array renewal over time (red chevrons)

Fig. 2

Maintenance of CENP-A within an evolving locus. Model of potential drivers of centromeric drift and instability. (A) Schematic representation of single-cell heterogeneity of CENP-A position at centromeres and neocentromeres, within otherwise identical cells. CENP-A (shades of red) is maintained with precision at both native centromeres and neocentromeres, for at least ~ 40 cell cycles. Following prolonged proliferation for ~ 280 cell cycles, representing several generations’ time scale, CENP-A evolves through drift, expansion and shrinkage of the CENP-A domain. While CENP-A evolves within a stable DNA methylation CDR at native centromeres, the DNA methylation CDR at neocentromeres is decoupled and lost over prolonged proliferation which may affect centromere function. (B) Single-cell CENP-A positions are accompanied by inversely correlated DNA methylation CDR that change in correlation with CENP-A enrichment. (C) Loss of heterochromatin marks such as H3K9me3, as a result of knocking out SUV39H1, SUV39H2 and SUZ12, disrupts the centromeric heterochromatin boundaries, resulting in CENP-A domain drift and expansion, as well as formation of new additional CENP-A domains