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    Topic review

    Centromere Flexibility

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    Submitted by: Laura Leo

    Definition

    Centromeres are the complex structures responsible for the proper segregation of chromosomes during cell division. Structural or functional alterations of the centromere cause aneuploidies and other chromosomal aberrations that can induce cell death with consequences on health and survival of the organism as a whole. Because of their essential function in the cell, centromeres have evolved high flexibility and mechanisms of tolerance to preserve their function following stress, whether it is originating from within or outside the cell.Despite the differences in DNA sequences, protein composition and centromere size, all of these diverse centromere structures promote efficient chromosome segregation, balancing genome stability and adaptability, and ensuring faithful genome inheritance at each cellular generation.

    1. Introduction

    Figure 1. Schematic representation of the functional role of Ash1, CBP, and Trx proteins in the centromeric region. These proteins work by modifying the epigenetic state of the centromeric chromatin. In particular, on H3 histones, Ash1 dimethylates lysine 4 (H3K4me2) and CBP acetylates lysine 27 (H3K27ac) within the centromeric region. Trx works by inducing chromatin opening which, in turn, favours both CENP-A/Cid deposition and activation of transcription.

    It has been shown that Sat III in both Drosophila and mammals, and centromeric transposons, are weakly transcribed [21][32], but it is not clear what their role in centromeric function could be. There is also the possibility that centromeres’ basal transcription is not causative but a mere consequence of the chromatin opening for Cid/CENP-A loading, without holding being necessary for centromeric functionality. However, given several studies have shown that the direct inhibition of centromeric RNAs causes overall reduction in CENP-A at centromeres [50][51][54][69][70][71][72][73][74], the alternative possibility would imply that transcription may be a consequence of chromatin opening, while transcription products play a direct role in CENP-A deposition and centromeric stability. Despite the differences in DNA sequences, proteins composition and centromere size, all of these diverse centromere structures promote efficient chromosome segregation, balancing genome stability and adaptability, and ensuring faithful genome inheritance at each cellular generation.

    3. Neocentromere as a Functional and Evolutionary Model for Centromere Biology

    How and why neocentromeres appear in a given chromosome region are intriguing questions. It has been proposed that de novo centromeres might represent different scenarios: “latent” centromeres [75][76][77], which are locations of ancestral centromeres following centromere repositioning events [78], (reviewed in [79]), or euchromatic regions, where centromeric markers have spread from adjacent areas, inducing neocentromere formation near endogenous centromeres. Some studies in Drosophila support the model that formation of the neocentromere may depend on the proximity to an endogenous centromere. However, some observations suggest that neocentromeres are often formed in distal chromosomal regions, usually separated from endogenous centromeres by long tracts of DNA, and they cannot be explained as formed by the spread of centromeric activity in cis [80].   A different model for neocentromere formation called the “lateral inhibition model” [81] supports the existence of many sites along a chromosome that are potentially able to perform centromeric activity, but that are normally repressed by a dominant centromere. It has been shown that a neocentromere is capable of forming near telomeres at the end of the chromosome [82]. This substantiates the hypothesis formulated by Agudo et al. [83] (reviewed in [84]) that the centromere evolved from telomere during the evolutionary origin of the eukaryotic chromosome. Recently, Palladino et al. [82] has shown that targeting Cal1 to chromosomal regions outside the original centromere induces the deposition of Cid and the formation of a new centromere at different locations, even at large genomic distance from the endogenous site. Zeitlin et al. [85] speculated that a neocentromere could emerge at site of breaks, following the observation that CENP-A is rapidly recruited to DNA double-strand breaks. This point of view is also supported by Ventura et al. [78], who noticed the closeness of the breakpoint to the neocentromere location in some studies. It has been shown that CENP-A is produced in excess of the needs for centromeres and that it is deposited around the original centromere and on islands of nucleosomes scattered along the chromosomes [21][86][87], only to be cleared during replication [21][88]. It is possible that some of these islands accumulate a quantity of CENP-A that predisposes them to acquire a potential centromeric function in case the endogenous centromere is damaged. In this case, not all chromosomal regions are equally and simultaneously predisposed to acquire a centromeric activity. Another mode of neocentromere formation may involve transposable elements (TE). Notably, stress induces the activation of TE, causing their transposition to new locations [41][89][90][91][92]. It is then possible that following chromosomal insult or rearrangements, a single TE may be sufficient to initiate CENP-A recruitment via its nascent transcription, breaks generation and other specific chromatin alterations associated with the “jump” and/or the TE reintegration into a new locus [64]. However, we favor an alternative hypothesis, that a random insertion of a TE per se does not trigger neocentromere formation unless it hits a CENP-A ectopic site. The concomitance of preexisting ectopic CENP-A and transposition may represent the first step towards the formation of a new centromere. Over time, the accumulation of other repetitive sequences through new transpositions or duplications of existing sequences in these CENP-A ectopic “hot spots” would create a genetic and epigenetic landscape for the evolution of a complex centromere that can functionally replace the endogenous one.

    4. Holocentromere

    Nematodes, some insects and species of plants belonging to the flowering plants have diffused centromeres throughout their chromosomes, and these are described as “holocentric”. From a cytological point of view, holocentric chromosomes do not present a primary constriction in metaphase—a hallmark narrowing found in stereotypical metacentric or sub-metacentric chromosomes—and do not have a designated place along the chromosome for spindle microtubule attachment. Instead, the whole chromosomal surface is bound and segregated. Genomic evidence suggests that many holocentric chromosomes lack tandem repeats and have cenH3 binding sites distributed over a wide variety of unique sequences throughout the chromosome, as expected. The nematode C. elegans is the exemplar case of a holocentric organism. Recently, the chromosomal localization of histone cenH3 was determined in C. elegans by ChIP–chip analysis [93]. It was found that ~50% of the genome can be associated with cenH3, showing complete absence of particular DNA sequences to control cenH3 incorporation. Fundamental studies on the regulation of diffuse centromeres have been carried out on the nematode Parascaris equorum. In this organism, as in C. elegans, development is strictly mosaic, and each cell performs a predetermined number of cell divisions before differentiation. A consequence of this developmental system is that an induced death of a single cell can be lethal to the embryo because it cannot be replaced at the embryonic stage. Furthermore, in Parascaris, there is the phenomenon of chromatin diminution in somatic cells, which does not occur in germ cells. In embryonic somatic cells, both terminal and intercalary heterochromatin with no detectable kinetochore activity is eliminated by fragmentation, producing about 60 small chromosomes that are equipped with centromeres and that segregate correctly during mitosis [94]. In gonial cells, heterochromatin is not eliminated, and both heterochromatin and euchromatin retain kinetochore activity. Finally, in meiotic cells, centromeric activity is restricted to the terminal heterochromatic regions to which the spindle microtubules attach in the absence of a kinetochore plate. Therefore, in Parascaris, there is both structural and regional variability in relation to the cell type. In the embryo’s somatic cells, the centromeric activity is restricted to euchromatin, while in gonial cells it is diffused over different chromatin environments, and in meiotic cells is restricted to telomeric heterochromatin. Therefore, Parascaris and other nematodes represent interesting models to study epigenetic centromere organization for the presence of three different centromere states under physiological conditions.

    5. Conclusions

    Proper segregation of chromosomes during cell division is essential for the survival of the cell and the whole organism. Therefore the centromere, a complex structure used for this function, has adapted during evolution to respond to changes in the cellular microenvironment as well to those in the external environment. The conflict between the need for functional stability and variability dictated by the environmental changes has been resolved with a wide flexibility through various epigenetic mechanisms. In order to keep the correct centromere functionality, epigenetic mechanisms can buffer possible centromere structural variations.

    This entry is adapted from 10.3390/genes11070809

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