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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE336584 | GEO | 2026/06/26

REPOSITORIES: GEO

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Genome-wide maps of CENP-A nucleosomes in three neocentromere-containing cell lines

Project description:We used native ChIP-seq of CENP-A-containing particles from normal centromeres on alpha-satellite DNA and three naturally-occurring neocentromeres to test the proposed models for the major form of the fundamental repeating unit of centromeric chromatin. We found that the predominant form of the CENP-A particle at the centromere is an octameric nucleosome with loose terminal DNA. Additionally, we found CENP-A nucleosomes are strongly phased on the 171 bp alpha-satellite monomers of normal centromeres, and also display strong positioning and neocentromeres. Comparison of CENP-A and bulk nucleosome DNA lengths and positions in three different human neocentromere-containing cell lines

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Genome-wide maps of CENP-A nucleosomes in three neocentromere-containing cell lines

2013-05-04 | GSE44724 | GEO

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2013-11-03 | E-GEOD-37094 | biostudies-arrayexpress

Epigenetic centromere identity is precisely maintained through DNA replication but is uniquely specified among human cells

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Epigenetically induced paucity of histone H2A.Z stabilizes fission yeast ectopic centromeres

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A high-resolution map of inner kinetochore proteins in fission yeast regional centromeres

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2015-08-17 | GSE64294 | GEO

The Ino80 complex mediates epigenetic centromere propagation via active removal of histone H3

Project description:Centromere is the chromosomal locus at which kinetochore is assembled to direct chromosome segregation. Histone H3 variant CENP-A epigenetically marks active centromeres; however, the mechanism by which CENP-A propagates at the centromere, replacing histone H3, remains poorly understood. Using fission yeast, we find that CENP-ACnp1 chromatin assembly at the centromere requires the Ino80 ATP-dependent chromatin remodeling complex which removes histone H3-containing nucleosomes from associated chromatin. CENP-ACnp1 chromatin actively recruits the Ino80 complex to centromeres to elicit eviction of histone H3-containing nucleosomes. Artificial targeting of Ino80 subunits to a non-centromeric DNA placed in a native centromere enhances the spreading of CENP-ACnp1 chromatin into the non-centromeric DNA. Based on these results, we propose that CENP-ACnp1 chromatin employs the Ino80 complex to mediate replacement of histone H3 with CENP-ACnp1, and thereby reinforces itself.

2017-07-14 | GSE99589 | GEO

Hap2-Ino80 mediated transcription facilitates de novo establishment of CENP-A chromatin

Project description:Centromeres are maintained epigenetically by the presence of CENP-A, an evolutionarily-conserved histone H3 variant, which directs kinetochore assembly and hence, centromere function. To identify factors that promote assembly of CENP-A chromatin, we affinity selected solubilised fission yeast CENP-ACnp1 chromatin. All subunits of the Ino80 complex were enriched, including the auxiliary subunit Hap2. In addition to a role in maintenance of CENP-ACnp1 chromatin integrity at endogenous centromeres, Hap2 is required for de novo assembly of CENP-ACnp1 chromatin on naïve centromere DNA and promotes H3 turnover on centromere regions and other loci prone to CENP-ACnp1 deposition. Prior to CENP-ACnp1 chromatin assembly, Hap2 is required for transcription from centromere DNA. These analyses suggest that Hap2-Ino80 destabilises H3 nucleosomes on centromere DNA through transcription-mediated histone H3 turnover, driving the replacement of resident H3 nucleosomes with CENP-ACnp1 nucleosomes. These inherent properties define centromere DNA by directing a program that mediates CENP-ACnp1 assembly on appropriate sequences.

2020-05-27 | PXD016602 | Pride

Dbp7 and RNA exosome subunit Dis3 interacts to mediate CENP-A loading via CENP-A chaperone Sim3

Project description:Background: Centromeres are crucial for proper chromosomes segregation during cell division. Centromeres in most eukaryotes are epigenetically specified by the histone 3 (H3) variant, CENP-A. How CENP-A precisely targets to centromeres remains elusive. Centromeres are typically transcribed into non-coding RNAs, which have been implicated in centromere functions. But the exact role of centromeric RNA in CENP-A loading is still poorly understood. In addition, centromere transcription induce formation of R-loops consisting of a DNA:RNA hybrid and a displaced single-stranded DNA. Excessive R-loops lead to genome instability. Little is known about the mechanism used for safeguarding centromeres against R-loops. Results: Here we show that through a visual genetic screen, we identified a conserved RNA binding protein Dbp7 that plays a critical role in CENP-A loading to centromeres. Deletion of dbp7+ results in CENP-A mislocalization and defects in chromosome segregation and centromere silencing. We found that Dbp7 associates with centromere transcripts, and further showed that Dbp7 prevents accumulation of R-loops at centromeres. Our domain-deletion analysis demonstrated that the DEAD-box helicase domain and the C-terminal extension motif of Dbp7 contribute to its role in centromere function. In addition, Dbp7 interacts with the key exosome subunit Dis3. Importantly, we found that Dis3 promotes CENP-A centromere loading by interacting the CENP-A chaperone Sim3. Conclusions: Together, this study uncovered a previously unrecognized CENP-A loading mechanism, by which Dbp7 and Dis3 bind to centromeric transcripts and in turn mediate recruitment of CENP-A via recruiting Sim3. Our work also provides mechanistic insight into R-loop resolution at centromeres.

2025-01-15 | GSE285031 | GEO

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