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Title: Epigenetically-Inherited Centromere and Neocentromere DNA Replicates Earliest in S-Phase}
Article:
Abstract:
Eukaryotic centromeres are maintained at specific chromosomal sites over many generations. In the budding yeast Saccharomyces cerevisiae, centromeres are genetic elements defined by a DNA sequence that is both necessary and sufficient for function; whereas, in most other eukaryotes, centromeres are maintained by poorly characterized epigenetic mechanisms in which DNA has a less definitive role. Here we use the pathogenic yeast Candida albicans as a model organism to study the DNA replication properties of centromeric DNA. By determining the genome-wide replication timing program of the C. albicans genome, we discovered that each centromere is associated with a replication origin that is the first to fire on its respective chromosome. Importantly, epigenetic formation of new ectopic centromeres( neocentromeres) was accompanied by shifts in replication timing, such that a neocentromere became the first to replicate and became associated with origin recognition complex( ORC) components. Furthermore, changing the level of the centromere-specific histone H3 isoform led to a concomitant change in levels of ORC association with centromere regions, further supporting the idea that centromere proteins determine origin activity. Finally, analysis of centromere-associated DNA revealed a replication-dependent sequence pattern characteristic of constitutively active replication origins. This strand-biased pattern is conserved, together with centromere position, among related strains and species, in a manner independent of primary DNA sequence. Thus, inheritance of centromere position is correlated with a constitutively active origin of replication that fires at a distinct early time. We suggest a model in which the distinct timing of DNA replication serves as an epigenetic mechanism for the inheritance of centromere position.
Introduction:
Centromeres are essential components of eukaryotic chromosomes required for proper chromosome segregation to daughter cells. Lack of a functional centromere, or the presence of multiple centromeres, renders chromosomes unstable and prone to mis-segregation and breakage. This genome instability is associated with carcinogenesis and can also result in cell death. An intriguing property of most eukaryotic centromeres that remains poorly explained is their mode of inheritance. In principle, the functional identity of a single locus on a chromosome, such as a centromere, requires that locus to have at least one unique property that distinguishes it from other loci on that chromosome. While a primary DNA consensus sequence would be sufficient to define a single locus per chromosome, most eukaryotic centromeres are not defined at the DNA sequence level( reviewed in[1]–[5]). Thus, for instance, centromeres on different chromosomes in any one species do not share primary DNA sequence between them; furthermore, centromeric DNA sequence diverges between closely-related species while centromeric loci remain syntenic; in rare cases, centromere proteins move to new loci that do not normally function as centromeres. These neocentromeres, which remain stable at their new ectopic loci, have been observed in humans as well as in several model organisms[6]–[8]. Rather than a specific DNA sequence, a unique, conserved histone H3 variant, termed CENP-A/CenH3( Cse4 in yeasts), distinguishes eukaryotic centromeres from the rest of the chromosome and has inspired the majority of current models of epigenetic centromere inheritance. These models propose that centromeric chromatin structure contains the information necessary to form and maintain centromeres at a given locus. One model suggests that CENP-A and histone H3 are expressed and/or deposited at different times during the cell cycle[9]–[12]. Consistent with this, S. pombe CENP-A expression reaches maximal levels just before the G1-S boundary[11] and can be deposited in either G1/early S-phase, or via a different pathway in G2[12]. A related hypothesis suggests that centromeric DNA might replicate at a distinct time during S-phase, and that this may be coordinated with the timing of CENP-A deposition[13]( reviewed in[14]). However, studies in flies and mammalian cells that utilized microscopy measurements of BrdU incorporation to follow the replication timing of centromeric DNA failed to detect a distinct time of replication at centromeres[9],[15]–[17] and thus such models were abandoned. It is important to note that these experiments may lack the resolution and precision necessary to detect replication events within specific regions of the genome. Replication timing microarrays could provide the necessary precision, however centromeres in most eukaryotes typically span hundreds to thousands of kilobases of highly repetitive DNA and are usually not fully sequenced, thereby obviating such analyses. In contrast, centromeres in the pathogenic yeast Candida albicans exhibit all the hallmarks of epigenetically inherited centromeres, yet are short( ∼ 3 kb), simple and fully sequenced[7],[18]–[21], making this yeast an attractive model system for the study of centromeric DNA properties. In this study, we used C. albicans to study the replication of centromeric DNA. We found that on all chromosomes, the centromere was associated with a replication origin that fires first, and well before all other origins, on that chromosome. Manipulating Cse4 binding by either deletion of a canonical centromere locus or by placing it under the control of a conditional promoter revealed that centromere determinants attract replication components and specify early DNA replication. In addition, we describe a sequence feature of C. albicans centromeres- asymmetrical nucleotide composition- that is indicative of stable replication activity over evolutionary time scales. Using phylogenetic comparison, we provide evidence linking the epigenetic inheritance of centromere position with replication activity. Thus, DNA replication timing can serve as the basis for the inheritance of functional centromeres at specific chromosomal sites, representing a novel mechanism of epigenetic inheritance.
Discussion:
This study provides the first comprehensive analysis of DNA replication of epigenetically-inherited centromeres. Our results show that centromeres replicate at a distinct time from the rest of the chromosome, centromeric determinants can change the replication time of the loci at which they reside, and the DNA replication properties of centromeres are linked to their epigenetic inheritance over evolutionary time scales. Based on this, we propose a self-reinforcing, positive-feedback loop model, in which centromeric determinants affect DNA replication timing and in turn, a distinct replication time facilitates the recruitment of centromeric determinants to that specific locus( Figure 5). Specifically, centromere site specification by Cse4 nucleosomes recruits factors that mediate replication initiation at a distinct time at the very beginning of S-phase( Figure 2). Furthermore, we speculate that early, distinctive replication timing, in turn enables subsequent deposition of centromere-specific proteins such as Cse4 nucleosomes at the region that is first to replicate, for instance due to elevated levels of these proteins in the very beginning of S-phase[11]–[14]. In particular, it has previously been shown in S. pombe that expression of Cse4 occurs from late-M to G1/S phase, and precedes maximal expression of histone H3 in S-phase[11]. Our calculations suggest that centromeric chromatin is replicated very rapidly- within the first <20 seconds of S-phase in C. albicans( Materials and Methods). Further studies will be required to link the distinct timing of CENP-A deposition and the time of centromere replication. This self-reinforcing association between centromere determinants and early replication timing does not require a particular underlying DNA sequence, establishing it as an epigenetic system. This epigenetic system determines centromere position, as well as replication timing and the constitutive nature of centromeric replication origins, which our results show for the first time can be determined epigenetically. Early and constitutive replication are directly related to each other, as a locus that replicates first will never be passively replicated and hence will be active in every cell cycle. The combination of constitutive origin activity and the relaxation of sequence constraints that stems from the epigenetic nature of this system, enables the underlying DNA to mutate at elevated rates, explaining previous observations that centromeric DNA mutates at high rates while centromere position remains unaltered[21],[30]. We now show that centromeric DNA in several yeast species mutates with a specific sequence bias due to the influence of a centromere-associated replication origin. We describe a novel type of epigenetic inheritance mechanism that is directly related to the fundamental mechanism of genetic inheritance in that both depend on DNA replication. Centromeres are maintained at specific chromosomal positions in a highly robust manner that is crucial for ensuring high-fidelity chromosome segregation; thus, this replication-timing-dependent epigenetic inheritance mechanism may confer a level of stability unprecedented for an epigenetic system. Finally, another attractive aspect of this model is that, instead of requiring a specialized mechanism for inheritance of centromeric nucleosomes outside of S-phase[11],[17], it directly connects centromeric nucleosome inheritance with DNA replication, similar to the inheritance of canonical nucleosomes that occurs following passage of the replication fork.
Centromeres form at the same chromosomal position from generation to generation , yet in most species this inheritance occurs in a DNA sequence–independent manner that is not well understood . Here , we determine the timing of DNA replication across the genome of the human fungal pathogen Candida albicans and find that centromeric DNA is the first locus to replicate on each chromosome . Furthemore , this unique replication timing may be important for centromere inheritance , based on several observations . First , DNA sequence patterns at centromeres indicate that , despite high levels of primary sequence divergence , the region has served as a replication origin for millions of years; second , formation of a neocentromere ( a new centromere formed at an ectopic locus following deletion of the native centromere DNA ) results in the establishment of a new , early-firing origin of replication; and third , a centromere-specific protein , Cse4p , recruits origin replication complex proteins in a concentration-dependent manner . Thus , centromere position is inherited by an epigenetic mechanism that appears to be defined by a distinctively early firing DNA replication origin .