Genetic and epigenetic regulation of centromeres: a look at HAC formation

Abstract

The centromere is a specialized chromosomal locus required for accurate chromosome segregation. A specific histone H3 variant, CENP-A, assembles at centromeres. CENP-A is required for kinetochore protein assembly and is an epigenetic marker for the maintenance of a functional centromere. Human CENP-A chromatin normally assembles on α-satellite DNA (alphoid DNA), a centromeric repetitive sequence. Using alphoid DNA arrays, human artificial chromosomes (HACs) have been constructed in human HT1080 cells and used to dissect the requirements for CENP-A assembly on DNA sequence. However, centromere formation is not a simple genetic event. In other commonly used human cell lines, such as HeLa and U2OS cells, no functional de novo centromere formation occurs efficiently with the same centromeric alphoid DNA sequences. Recent studies using protein tethering combined with the HAC system and/or genetic manipulation have revealed that epigenetic chromatin regulation mechanisms are also involved in the CENP-A chromatin assembly pathway and subsequent centromere/kinetochore formation. We summarize the DNA sequence requirements for CENP-A assembly and discuss the epigenetic regulation of human centromeres.

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Abbreviations

Alphoid DNA:

Alpha satellite DNA

ARS:

Autonomous replicating sequence

CAD:

CENP-A distal

CCAN:

Constitutive centromere-associated network

CDE:

Conserved DNA element

CENP:

Centromere protein

HAC:

Human artificial chromosome

HOR:

Higher order repeat

ICEN:

Interphase Centromere Complex

KMN:

KNL-1/Mis12 complex/Ndc80

NAC:

CENP-A nucleosome-associated complex

YAC:

Yeast artificial chromosome

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Acknowledgments

We would like to express our gratitude to Drs. Beth Sullivan and Natalay Kouprina for giving us the opportunity to write this review article. Due to space constraints, it was not possible to cite all of the excellent work in this area and we regret omitting mention of many valuable studies in the field of human artificial chromosome technology/biology. This work was supported in part by MEXT KAKENHI Japan (grant numbers 23247030 and 23114008 to H.M.), the Kazusa DNA Research Institute Foundation (H.M.) and Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, USA (V.L.). W.C.E. is a Principal Research Fellow of The Wellcome Trust [grant number 073915].

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Correspondence to Hiroshi Masumoto.

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Responsible Editors: Natalay Kouprina and Vladimir Larionov.

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Ohzeki, Ji., Larionov, V., Earnshaw, W.C. et al. Genetic and epigenetic regulation of centromeres: a look at HAC formation. Chromosome Res 23, 87–103 (2015). https://doi.org/10.1007/s10577-015-9470-z

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Keywords

  • Centromere
  • CENP-A
  • HAC
  • Kinetochore
  • Heterochromatin
  • CENP-B
  • HAT