Abstract
Human centromeres are multi-megabase regions of highly ordered arrays of alpha satellite DNA that are separated from chromosome arms by unordered alpha satellite monomers and other repetitive elements. Complexities in assembling such large repetitive regions have limited detailed studies of centromeric chromatin organization. However, a genomic map of the human X centromere has provided new opportunities to explore genomic architecture of a complex locus. We used ChIP to examine the distribution of modified histones within centromere regions of multiple X chromosomes. Methylation of H3 at lysine 4 coincided with DXZ1 higher order alpha satellite, the site of CENP-A localization. Heterochromatic histone modifications were distributed across the 400–500 kb pericentromeric regions. The large arrays of alpha satellite and gamma satellite DNA were enriched for both euchromatic and heterochromatic modifications, implying that some pericentromeric repeats have multiple chromatin characteristics. Partial truncation of the X centromere resulted in reduction in the size of the CENP-A/Cenp-A domain and increased heterochromatic modifications in the flanking pericentromere. Although the deletion removed ∼1/3 of centromeric DNA, the ratio of CENP-A to alpha satellite array size was maintained in the same proportion, suggesting that a limited, but defined linear region of the centromeric DNA is necessary for kinetochore assembly. Our results indicate that the human X centromere contains multiple types of chromatin, is organized similarly to smaller eukaryotic centromeres, and responds to structural changes by expanding or contracting domains.
Highlights
The centromere is a crucial locus for maintaining genome stability
Each located 150 kb outside of the centromere, one in Xp (ZXDA) and one in Xq, were non-centromeric assay points. Since these sites are located outside the centromere, we expected to observe a shift from centromeric histone modifications to those more indicative of euchromatin
Histone modifications correlated with open or repressive chromatin were assayed at intervals spanning the centromeric genome assembly on multiple X chromosomes
Summary
The centromere is a crucial locus for maintaining genome stability. It is the foundation for kinetochore formation, and directs the proper chromosomal segregation during cell division. Centromeres are essential loci that are functionally similar, they show little consistency in DNA sequence content, ranging from the sequence-dependent 125 bp point centromere in the budding yeast Saccharomyces cerevisiae to multi-megabase, epigeneticallyregulated regional centromeres in primates [4]. Replacement of core histones with histone variants, as well as posttranslational, covalent modification (acetylation, phosphorylation, methylation and ubiquitination) of the amino-terminal tails of histones correlate with distinctive chromatin states, such as transcriptionally repressive heterochromatin and open euchromatin that supports transcription [6]. Centromeres contain the histone H3 variant, CENP-A that replaces core H3 within centromeric nucleosomes. A similar model for centromere organization is present in other organisms, such as fission yeast and Drosophila [9,10]
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