Epigenetic specification of centromeres.

Centromeres are the discrete sites of spindle microtubule attachment on chromosomes during mitosis and meiosis in all eukaryotes. These highly specialized chromatin structures typically occupy the same site for thousands of generations, yet the mechanism by which centromeres are established, maintained, and function remain a mystery. In metazoans, centromeric DNA sequence has proven not to be the key determinant of centromeric identity; therefore, centromeres are thought to be epigenetically specified by their specialized chromatin structure. In all eukaryotes, the centromere-specific histone H3 variant CenH3 replaces canonical H3 within nucleosomes at centric chromatin. This specialized nucleosome is the building block upon which all other centromere-associated proteins depend. This review highlights exciting new findings that have resulted in a paradigm shift in our understanding of CenH3 assembly into centromeric chromatin, CenH3 nucleosomal structure, CenH3 chromatin folding, the contribution of these factors to centromeric identity, and finally, the intimate role cell-cycle-regulated transcription and pericentric heterochromatin play in the maintenance and integrity of centromeres.