KAT7/HBO1/MYST2 Regulates CENP-A Chromatin Assembly by Antagonizing Suv39h1-Mediated Centromere Inactivation

Centromere chromatin containing histone H3 variant CENP-A is required for accurate chromosome segregation as a foundation for kinetochore assembly. Human centromere chromatin assembles on a part of the long α-satellite (alphoid) DNA array, where it is flanked by pericentric heterochromatin. Heterochromatin spreads into adjacent chromatin and represses gene expression, and it can antagonize centromere function or CENP-A assembly. Here, we demonstrate an interaction between CENP-A assembly factor M18BP1 and acetyltransferase KAT7/HBO1/MYST2. Knocking out KAT7 in HeLa cells reduced centromeric CENP-A assembly. Mitotic chromosome misalignment and micronuclei formation increased in the knockout cells and were enhanced when the histone H3-K9 trimethylase Suv39h1 was overproduced. Tethering KAT7 to an ectopic alphoid DNA integration site removed heterochromatic H3K9me3 modification and was sufficient to stimulate new CENP-A or histone H3.3 assembly. Thus, KAT7-containing acetyltransferases associating with the Mis18 complex provides competence for histone turnover/exchange activity on alphoid DNA and prevents Suv39h1-mediated heterochromatin invasion into centromeres. [Display omitted] •The histone acetyltransferase KAT7 positively regulates centromeric CENP-A assembly•Human Mis18 complex is a scaffold for assembly of KAT7 and HJURP, a CENP-A chaperone•KAT7 or RSF1 stimulates histone turnover/exchange on alphoid DNA•KAT7 antagonizes H3K9-trimethylase Suv39h1-mediated centromere inactivation Human centromeres contain histone H3 variant CENP-A and are flanked by pericentric heterochromatin. Spreading of heterochromatin into the centromere can impede centromere function. Ohzeki et al. demonstrate that the KAT7 histone acetyltransferase promotes CENP-A assembly and preserves centromere function by preventing H3K9-trimethylase Suv39h1-mediated heterochromatin invasion via a histone turnover mechanism.