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Epigenetic activation and inactivation of centromeres.

The centromere is the chromosomal region where the kinetochore forms. The kinetochore is a protein structure mediating contacts with the mitotic and meiotic spindle microtubule structures, enabling separation of chromosomes in mitosis and meiosis. Failure of the chromosome segregation machinery either by inactivation of the centromere or malfunction of the kinetochore or spindle results in chromosome mis-segregation and aneuploidy of the daughter cells. Aneuploidy is associated with birth defects or cancer. Genome stability can also be compromised by activation of extra centromeres (neocentromeres). Thus, to ensure euploidy and correct chromosome segregation, epigenetic activation of a single centromere per chromosome is required. The centromere is marked epigenetically by incorporation of the histone H3 variant CENP-A in the centromeric chromatin. In most organisms endogenous centromeres are surrounded and stabilized by adjacent heterochromatin, together constituting regional centromeres. In some organisms, such as budding yeast, point centromeres of a single nucleosome exist without pericentric heterochromatin. Yet, in other organisms, for example the worm C. elegans, the entire chromosome forms a holocentric centromere [1]. The centromere and kinetochore proteins are highly conserved in eukaryotes and the underlying DNA sequence is composed of complex repeats in most organisms. By contrast with the conserved proteins, the repetitive sequences are highly variable, both between species and individuals [2]. For technical reasons, endogenous human centromeres have been challenging to study and most of the mechanistic insights come from studies of human artificial chromosomes or centromeres in genetically amenable model organisms, such as budding and fission yeasts and the fruit fly. In fission yeast for example, the borders between CENP-A chromatin and the surrounding heterochromatin are clearly defined and the underlying DNA repeats are distinct. However, in human cells, the alpha satellite repeats make up the majority of the centromere DNA and heterochromatin is interspersed with CENP-A chromatin. Recent technical advances such as the delineation of the human centromere repeats, superresolution microscopy and the proximity ligation assay allow us to embark on more detailed examinations of the regulation of the human centromere and how it might contribute to disease. For an acentric chromosome fragment to be propagated through somatic cell divisions and through the germ line of a eukaryotic organism, a new centromere needs to form. A so-called ‘neocentromere’ is a functional centromere structure that forms at a nontypical genomic region and at DNA sequences that may differ from endogenous centromeres [3]. Such neocentromeres have been observed to spontaneously occur in several cancers characterized by genetically instability [4] and, occasionally, in cells that have gone through many cell divisions. Alternatively, the centromere formation can be studied experimentally by artificially removEpigenetic activation and inactivation of centromeres