Epigenetic Inheritance of Centromeres

Abstract

Centromeres of higher eukaryotes are epigenetically maintained; however, the mechanism that underlies centromere inheritance is unknown. Centromere identity and inheritance require the assembly of nucleosomes containing the CenH3 histone variant in place of canonical H3. Work from our laboratory has led to the proposal that epigenetic inheritance of centromeres evolved as adaptations of CenH3 and other centromere proteins to resist drive of selfish centromeres during female meiosis. Our molecular studies have revealed that the Drosophila CenH3 nucleosome is equivalent to half of the canonical H3 nucleosome and induces positive supercoils, as opposed to the negative supercoils induced by an H3 nucleosome. CenH3 likewise induces positive supercoils in functional yeast centromeres in vivo. The right-handed wrapping of DNA around the histone core implied by positive supercoiling indicates that centromeric nucleosomes are unlikely to be octameric and that the exposed surfaces holding the nucleosome together would be available for kinetochore protein recruitment. The mutual incompatibility of nucleosomes with opposite topologies could explain how centromeres are efficiently maintained as unique loci on chromosomes. We propose that the opposite wrapping of DNA around a half-nucleosome core particle facilitates a mode of inheritance that does not depend on DNA sequence, DNA modification or protein conformation.

The Composition, Functions, and Regulation of the Budding Yeast Kinetochore

“…There are three conserved centromere-determining elements (CDE): an 8-bp palindrome called CDEI, a 78-to 86-bp stretch of AT-rich (.90%) DNA called CDEII, and a conserved 26-bp element called CDEIII (Figure 4) (Clarke 1998). Although most eukaryotic centromeres are maintained epigenetically (Black et al 2010;Henikoff and Furuyama 2010), yeast centromeres are genetically specified by DNA sequence. The CDEI consensus sequence (PuTCACPuTG) binds to the helix-loop-helix protein Cbf1 (Cai and Davis 1989;Baker and Masison 1990;Cai and Davis 1990), a transcription factor that also binds to other elements throughout the genome.…”

Structure of a CENP-A–histone H4 heterodimer in complex with chaperone HJURP

“…The precise model of CENP-A-containing nucleosomes is still a matter of debate (Henikoff and Furuyama 2010;Black and Cleveland 2011). A closely relevant point here is whether a centromeric nucleosome contains a CENP-A-H4 heterodimer or heterotetramer (Dimitriadis et al 2010;Sekulic et al 2010).…”

Ectopic Centromere Nucleation by CENP-A in Fission Yeast

“…However, most other eukaryotes contain regional centromeres, which are more complex and usually consist of large blocks of repetitive DNA sequences (Pluta et al 1995;Henikoff et al 2001). Epigenetic mechanisms appear to play a dominant role in the formation and inheritance of regional centromeres (Allshire and Karpen 2008;Henikoff and Furuyama 2010).Centromere protein-A (CENP-A), a centromere-specific histone 3 (H3) variant, has been proposed to act as the epigenetic mark for centromere positioning (Palmer et al 1991;Henikoff and Furuyama 2010;Burrack and Berman 2012;Muller and Almouzni 2014). CENP-A partially replaces canonical histone H3 at the centromere and provides the structural and functional foundation for the assembly of the kinetochore (Black and Cleveland 2011;Maddox et al 2012).…”

“…It is vital for the proper segregation of chromosomes during mitosis and meiosis (Allshire and Karpen 2008;Henikoff and Furuyama 2010). Most eukaryotic chromosomes contain a single centromere that is faithfully inherited at the same position within the chromosome through generations.…”