Inheritance of the CENP-A chromatin domain is spatially and temporally constrained at human centromeres

Ross, Justyne; Woodlief, Kaitlin Stimpson; Sullivan, Beth A.

doi:10.1186/s13072-016-0071-7

Cited by 37 publications

(45 citation statements)

References 51 publications

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“…CENP-A nucleosomes appear to spread only far enough to create a centromeric chromatin domain that will confer chromosome stability. It appears that once the centromeric chromatin domain was established on the del(17), it has remained largely static, suggesting that centromere formation on non-centromeric sequences follows similar rules of inheritance at endogenous centromeres (Ross et al, 2016). …”

Section: Discussionmentioning

confidence: 99%

“…The molecular sizes of D17Z1 in L65-14A (3.7Mb) and L65-13A (0.7 Mb) had been previously calculated (Wevrick et al, 1990) and re-confirmed in our lab (Aldrup-MacDonald et al, in press ). Cenp-A domain size was calculated from the ratio of the length of Cenp-A antibody signal over the length of the D17Z1 array signal (Sullivan et al, 2011, Ross et al, 2016)…”

Section: Methodsmentioning

confidence: 99%

“…The H3 within centromeric chromatin carries post-translational modifications, including methylation of lysine 4 (K4), lysine 36 (K36), and to a lesser extent lysine 27 (K27), that are needed for centromeric transcription, centromere protein recruitment, and establishment of distinct chromatin domains within the broader centromere region (Bergmann et al, 2011, Ohzeki et al, 2012, Ohzeki et al, 2016) Although chromosome-specific alpha satellite arrays extend for several megabases within a given human centromere region, centromeric chromatin and centromere proteins are positioned on only 30–45% of the large repetitive array (Zeng et al, 2004, Lam et al, 2006a, Mravinac et al, 2009, Sullivan et al, 2011). Moreover, the CENP-A chromatin domain appears to be relatively fixed at a similar position on a given chromosome-specific array in different individuals (Ross et al, 2016). Restriction of centromeric chromatin suggests that only a limited section of alpha satellite DNA is required for proper centromere function in humans.…”

Section: Introductionmentioning

confidence: 99%

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Human centromere repositioning within euchromatin after partial chromosome deletion

et al. 2016

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Centromeres are defined by a specialized chromatin organization that includes nucleosomes that contain the centromeric histone variant CENP-A instead of canonical histone H3. Studies in various organisms have shown that centromeric chromatin (i.e. CENP-A chromatin or centrochromatin) exhibits plasticity, in that it can assemble on different types of DNA sequences. However, once established on a chromosome, the centromere is maintained at the same position. In humans, this location is the highly homogeneous repetitive DNA alpha satellite. Mislocalization of centromeric chromatin to atypical locations can lead to genome instability, indicating that restriction of centromeres to a distinct genomic position is important for cell and organism viability. Here, we describe a rearrangement of Homo sapiens chromosome 17 (HSA17) that has placed alpha satellite DNA next to euchromatin. We show that on this mutant chromosome, CENP-A chromatin has spread from the alpha satellite into the short arm of HSA17, establishing a ~700kb hybrid centromeric domain that spans both repetitive and unique sequences and changes the expression of at least one gene over which it spreads. Our results illustrate the plasticity of human centromeric chromatin and suggest that heterochromatin normally constrains CENP-A chromatin onto alpha satellite DNA. This work highlights that chromosome rearrangements, particularly those that remove the pericentromere, create opportunities for centromeric nucleosomes to move into non-traditional genomic locations, potentially changing the surrounding chromatin environment and altering gene expression.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Human centromere repositioning within euchromatin after partial chromosome deletion

et al. 2016

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“…Of course, the centromere formed at a given variant D17Z1 array might reflect several of these organizational scenarios. We recently showed that CENPA chromatin is assembled and maintained at the same general region of alpha satellite DNA (Ross et al 2016), so a key question is if D17Z1 array variation disrupts the largely static placement of centromeric chromatin on HSA17.…”

Section: Genomic Variation Affects Centromere Functionmentioning

confidence: 99%

Genomic variation within alpha satellite DNA influences centromere location on human chromosomes with metastable epialleles

et al. 2016

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Alpha satellite is a tandemly organized type of repetitive DNA that comprises 5% of the genome and is found at all human centromeres. A defined number of 171-bp monomers are organized into chromosome-specific higher-order repeats (HORs) that are reiterated thousands of times. At least half of all human chromosomes have two or more distinct HOR alpha satellite arrays within their centromere regions. We previously showed that the two alpha satellite arrays of Homo sapiens Chromosome 17 (HSA17), D17Z1 and D17Z1-B, behave as centromeric epialleles, that is, the centromere, defined by chromatin containing the centromeric histone variant CENPA and recruitment of other centromere proteins, can form at either D17Z1 or D17Z1-B. Some individuals in the human population are functional heterozygotes in that D17Z1 is the active centromere on one homolog and D17Z1-B is active on the other. In this study, we aimed to understand the molecular basis for how centromere location is determined on HSA17. Specifically, we focused on D17Z1 genomic variation as a driver of epiallele formation. We found that D17Z1 arrays that are predominantly composed of HOR size and sequence variants were functionally less competent. They either recruited decreased amounts of the centromere-specific histone variant CENPA and the HSA17 was mitotically unstable, or alternatively, the centromere was assembled at D17Z1-B and the HSA17 was stable. Our study demonstrates that genomic variation within highly repetitive, noncoding DNA of human centromere regions has a pronounced impact on genome stability and basic chromosomal function.

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“…The location of the centromere is highly fixed on the chromosome, with new CENP-A nucleosomes assembled near the domain of existing CENP-A [45]. The selective deposition of new CENP-A at the existing centromere is achieved by coupling the proteins required for CENP-A deposition to CCAN proteins, including CENP-A itself.…”

Section: Cell Cycle Control Of Centromere Inheritancementioning

confidence: 99%

Posttranslational mechanisms controlling centromere function and assembly

Srivastava

Zasadzińska

Foltz

2018

Current Opinion in Cell Biology

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Accurate chromosome segregation is critical to ensure the faithful inheritance of the genome during cell division. Human chromosomes distinguish the location of the centromere from general chromatin by the selective assembly of CENP-A containing nucleosomes at the active centromere. The location of centromeres in most higher eukaryotes is determined epigenetically, independent of DNA sequence. CENP-A containing centromeric chromatin provides the foundation for assembly of the kinetochore that mediates chromosome attachment to the microtubule spindle and controls cell cycle progression in mitosis. Here we review recent work demonstrating the role of posttranslational modifications on centromere function and CENP-A inheritance via the direct modification of the CENP-A nucleosome and pre-nucleosomal complexes, the modification of the CENP-A deposition machinery and the modification of histones within existing centromeres.

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Inheritance of the CENP-A chromatin domain is spatially and temporally constrained at human centromeres

Cited by 37 publications

References 51 publications

Human centromere repositioning within euchromatin after partial chromosome deletion

Human centromere repositioning within euchromatin after partial chromosome deletion

Genomic variation within alpha satellite DNA influences centromere location on human chromosomes with metastable epialleles

Posttranslational mechanisms controlling centromere function and assembly

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