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Chromosomes: Keeping Centromeric Identity

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Chromosomes: Keeping Centromeric Identity RESEARCH HIGHLIGHTS Nature Reviews Molecular Cell Biology | AOP, published online 3 May 2012; doi:10.1038/nrm3356 CHROMOSOMES authors found that these epigenetic states were altered at the centromere in MEFs lacking MIS18α, which suggests Keeping centromeric identity that MIS18α is important to maintain centromeric chromatin states. During cell division, the mitotic generated conditional knockout Moreover, Kim et al. identified DNMT3A spindle attaches to chromosomes mice for Mis18a (which encodes one and DNMT3B as MIS18α interacting at centromeric regions to ensure of three MIS18 subunits) . Knockout proteins . Centromeric localization of accurate chromosome segregation. embryos died around embryonic DNMT3A and DNMT3B was reduced In higher eukaryotes, the centromere day 3.5 and knockout blastocysts grown in Mis18a-deficient MEFs, and, vice is defined by the composition in vitro showed severe chromosomal versa, knockdown of Dnmt3a and and structure of the chromatin, missegregation and lack of centromeric Dnmt3b reduced MIS18α levels at the which in this case contains the CENPA, which ultimately caused cell centromere. This suggests that MIS18α histone H3 variant centromeric death. Interestingly, this phenotype and the DNA demethylases cooperate to protein A (CENPA). The mechanisms is almost identical to that of embryos localize at the centromere. underlying CENPA deposition to lacking CENPA, which confirms a Mis18α was found to interact with specify centromere identity are still functional link between MIS18α and these DNA demethylases through a poorly understood. Now, Kim et al. CENPA. Leu-rich region located at its carboxyl show that the mammalian MIS18 The authors further investigated terminus. Importantly, knockout MEFs complex functions by interacting with the function of MIS18α in conditional expressing Mis18a mutated at this DNA demethylases DNMT3A and Mis18a knockout mouse embryonic C-terminal region were hypomethylated DNMT3B to ensure their centromeric fibroblasts (MEFs). Consistent with their at the centromere and showed defects in localization and thus the epigenetic observations in cultured blastocysts, CENPA centromeric localization. states of centromeric chromatin that mutant MEFs showed abnormal Together, these results show that are required for CENPA loading. chromosome segregation and strongly DNMT3A- and DNMT3B-mediated The MIS18 complex has been reduced centromeric localization of DNA methylation at the centromere is previously shown to accumulate at the CENPA. Furthermore, MEFs arrested required for centromeric localization centromere during anaphase to early in mitosis showed defects in the of CENPA and that MIS18α interacts G1 phase, slightly ahead of CENPA organization of centromeric regions. with these DNA demethylases at the loading, and to be required for the Centromeres have both centromere to ensure their centromeric localization of CENPA at centromeres. heterochromatic characteristics, localization. Thus, these studies To assess the physiological role of such as H3 Lys9 trimethylation reinforce the hypothesis that the MIS18, Kim et al. and highly methylated MIS18 complex functions to propagate DNA, and euchromatic centromeric identity. characteristics, such as H3 Kim Baumann Lys4 dimethylation, both ORIGINAL RESEARCH PAPER Kim, I. S. et al. of which are important Roles of MIS18α in epigenetic regulation of for centromere and centromeric chromatin and CENP-A loading. kinetochore function. Mol. Cell 17 Apr 2012 (doi:10.1016/j. molcel.2012.03.021) Interestingly, the MACMILLAN\David Tolley NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 13 | JUNE 2012 © 2012 Macmillan Publishers Limited. All rights reserved.
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