Epigenetic mechanisms of centromeric chromatin assembly and chromosome segregation
Accurate chromosome segregation is critical to ensure the faithful inheritance of the genome during cell division and guard against genomic instability associated with cancer. Centromeric chromatin defines the site of kinetochore formation and ensures faithful chromosome segregation. In most eukaryotes, deposition of centromere specific nucleosomes containing the histone H3 variant CENP-A serves as an epigenetic mark critical for centromere specification and inheritance, independent of the underlying DNA sequence CENP-A containing centromeric chromatin provides the foundation for assembly of the constitute centromere and the kinetochore. Our lab is interested in understanding how centromeric nucleosomes distinguish centromeric chromatin from general chromatin, how centromeric identity is maintained and how these processes are altered in cancer. Posttranslational modification of histones amino-termini are key steps in regulating chromatin function. Our data demonstrate that centromeric nucleosomes undergo N-terminal tri-methylation, distinct from general chromatin. N-terminal methylation of CENP-A contributes centromere function through regulation of constitutive centromere protein recruitment. The mechanisms of assembly and retention of CENP-A nucleosomes are key factors in stable inheritance of centromere location, and ultimately the stability of the genome. DNA replication presents a challenge for inheritance of centromeric identity, as it does for all epigenetically encoded information, because nucleosomes are removed to allow for replication fork progression. Our recent data demonstrate a combined requirement for the MCM2-7 helicase complex and the CENP-A chaperone HJURP for inheritance of the centromeric epigenetic state through DNA synthesis.