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Epigenetic landscape of synthetic human centromeres: Euchromatic modifications coexist interdependently at CENP-A dense regions and prevent intrusion of other modifications [ChIP-seq]

ABSTRACT: Centromere is specialized chromatin structure essential for equal chromosome segregation. Human centromere is organized on a portion of homogeneously repeated DNA sequence, and contains nucleosomes including centromere specific histone H3, CENP-A. Histone modifications around the CENP-A dense region are also thought to have important roles in centromere function. Here, we used human artificial chromosome (HAC) technology to create functional centromeric chromatin on a synthetic centromeric repeat DNA sequence that allowed for structural analysis at 2-kb resolution. Analysis using this HAC centromere showed that the CENP-A dense regions are approximately 18–50 kb in size and coexisted with euchromatic histone modifications in a mutually dependent manner. We also find that when DNA replication reduces CENP-A density, a heterochromatin modification H3K9me3 transiently intrudes CENP-A-dense regions, and that both the CENP-A deposition factor HJURP and the histone acetyltransferase KAT7 are important for pushing back this intrusion. The synthetic centromere DNA generated in this study is more effective at elucidating centromere chromatin structure than relying on naturally occurring DNA mutations, allowing for a more precise understanding and manipulation of centromere function.

ORGANISM(S): Homo sapiens

PROVIDER: GSE287042 | GEO | 2026/07/08

REPOSITORIES: GEO

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Epigenetic landscape of synthetic human centromeres: Euchromatic modifications coexist interdependently at CENP-A dense regions and prevent intrusion of other modifications [DNA-seq]

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2014-04-07 | E-GEOD-44594 | biostudies-arrayexpress

The N-terminal Tail of CENP-A Confers Epigenetic Stability to Centromeres via the CENP-T Branch of the CCAN in Fission Yeast

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Neocentromeres fail to maintain DNA methylation boundaries, driving CENP-A drift, instability, and chromosome missegregation

Project description:Centromere identity is specified by CENP-A, a histone H3 variant that epigenetically defines centromere position. How CENP-A is maintained at one location in rapidly evolving centromeric DNA is unknown. Using single-cell derived clones of human cell lines, we demonstrate heterogeneity in CENP-A position within cell populations at neocentromeres and a native centromere. CENP-A heterogeneity is accompanied by heterogenous DNA methylation patterns, with DNA methylation shifting according to CENP-A position. We demonstrate centromere epigenetic plasticity over extended proliferation, with native centromeres maintaining stable DNA methylation boundaries, but neocentromeres exhibiting DNA methylation instability, boundary loss and increased missegregation. Finally, we show that neocentromeres are more sensitive to DNA methylation inhibition than native centromeres, and that this inhibition is accompanied by expanded CENP-A-enriched domains and increased missegregation. This study supports a role for DNA methylation boundaries in maintaining centromere position, stability and function and highlights the intrinsic instability of DNA methylation at neocentromeres.

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The 19S proteasome subunit Rpt3 regulates distribution of CENP-A by associating with centromeric chromatin

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Project description:CENP-A is a centromere-specific histone 3 variant essential for centromere specification. CENP-A partially replaces canonical histone H3 at the centromeres. How the particular CENP-A/H3 ratio at centromeres is precisely maintained is unknown. It also remains unclear how CENP-A is excluded from non-centromeric chromatin. Here we identify Ccp1, an uncharacterized NAP family protein in fission yeast that antagonizes CENP-A loading at both centromeric and non-centromeric regions. Like the CENP-A loading factor HJURP, Ccp1 interacts with CENP-A, and is recruited to centromeres at the end of mitosis in a Mis16-dependent manner. These data indicate that factors with opposing CENP-A loading activities are recruited to centromeres. Furthermore, Ccp1 also cooperates with H2A.Z to evict CENP-A assembled in euchromatin. Structural analyses indicate that Ccp1 forms a homodimer that is required for its anti-CENP-A loading activity. Our study establishes mechanisms for maintenance of CENP-A homeostasis at centromeres and the prevention of ectopic assembly of centromeres.

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