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CENP-A nucleosomes localize to transcription factor hotspots and subtelomeric sites in human cancer cells.

Athwal RK, Walkiewicz MP, Baek S, Fu S, Bui M, Camps J, Ried T, Sung MH, Dalal Y - Epigenetics Chromatin (2015)

Bottom Line: To investigate native CENP-A overexpression, we sought to uncover CENP-A-associated defects in human cells.A distinct class of CENP-A hotspots also accumulates at subtelomeric chromosomal locations, including at the 8q24/Myc region long-associated with genomic instability.These findings suggest that ectopic CENP-A nucleosomes could alter the state of the chromatin fiber, potentially impacting gene regulation and chromosome fragility.

View Article: PubMed Central - PubMed

Affiliation: Chromatin Structure and Epigenetics Mechanisms Unit, Center for Cancer Research, National Cancer Institute National Institutes of Health, 41 Center Drive, Bethesda, MD 20892 USA ; Laboratory of Receptor Biology and Gene Expression, Center for Cancer Research, National Cancer Institute National Institutes of Health, 41 Center Drive, Bethesda, MD 20892 USA.

ABSTRACT

Background: The histone H3 variant CENP-A is normally tightly regulated to ensure only one centromere exists per chromosome. Native CENP-A is often found overexpressed in human cancer cells and a range of human tumors. Consequently, CENP-A misregulation is thought to contribute to genome instability in human cancers. However, the consequences of such overexpression have not been directly elucidated in human cancer cells.

Results: To investigate native CENP-A overexpression, we sought to uncover CENP-A-associated defects in human cells. We confirm that CENP-A is innately overexpressed in several colorectal cancer cell lines. In such cells, we report that a subset of structurally distinct CENP-A-containing nucleosomes associate with canonical histone H3, and with the transcription-coupled chaperones ATRX and DAXX. Furthermore, such hybrid CENP-A nucleosomes localize to DNase I hypersensitive and transcription factor binding sites, including at promoters of genes across the human genome. A distinct class of CENP-A hotspots also accumulates at subtelomeric chromosomal locations, including at the 8q24/Myc region long-associated with genomic instability. We show this 8q24 accumulation of CENP-A can also be seen in early stage primary colorectal tumors.

Conclusions: Our data demonstrate that excess CENP-A accumulates at noncentromeric locations in the human cancer genome. These findings suggest that ectopic CENP-A nucleosomes could alter the state of the chromatin fiber, potentially impacting gene regulation and chromosome fragility.

No MeSH data available.


Related in: MedlinePlus

Genome-wide distribution of ectopic CENP-A hotspots across human chromosomes. Ectopic CENP-A clusters (gray boxes) at pericentromeric and subtelomeric regions of most human chromosomes in SW480, but not in HeLa or normal colon cells.
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Fig7: Genome-wide distribution of ectopic CENP-A hotspots across human chromosomes. Ectopic CENP-A clusters (gray boxes) at pericentromeric and subtelomeric regions of most human chromosomes in SW480, but not in HeLa or normal colon cells.

Mentions: DNA analysis of ectopic CENP-A hotspots demonstrates enrichment of CpG density and transcription factor binding motifs. (A) Ectopic CENP-A associated DNA is moderately enriched in CpG motifs. Window shows CpG motifs enriched in a scanning 10 bp window from an overlay of all hotspots (B) Left: TOMTOM DNA Motif analysis of CENP-A hotspots in SW480 and HeLa cells. Right: Pie charts showing similarity of identified hotspots to known classes of transcription factor binding sites. Detailed data for analysis of hotspots can be found in Table 5. Additional file1 contains the full list of hotspots, and a genome-wide overview is in Figure 7. (C) A list of other TOMTOM consensus motifs that correlate to the motifs identified in CENP-A hotspots includes chromatin effector proteins.


CENP-A nucleosomes localize to transcription factor hotspots and subtelomeric sites in human cancer cells.

Athwal RK, Walkiewicz MP, Baek S, Fu S, Bui M, Camps J, Ried T, Sung MH, Dalal Y - Epigenetics Chromatin (2015)

Genome-wide distribution of ectopic CENP-A hotspots across human chromosomes. Ectopic CENP-A clusters (gray boxes) at pericentromeric and subtelomeric regions of most human chromosomes in SW480, but not in HeLa or normal colon cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4363203&req=5

Fig7: Genome-wide distribution of ectopic CENP-A hotspots across human chromosomes. Ectopic CENP-A clusters (gray boxes) at pericentromeric and subtelomeric regions of most human chromosomes in SW480, but not in HeLa or normal colon cells.
Mentions: DNA analysis of ectopic CENP-A hotspots demonstrates enrichment of CpG density and transcription factor binding motifs. (A) Ectopic CENP-A associated DNA is moderately enriched in CpG motifs. Window shows CpG motifs enriched in a scanning 10 bp window from an overlay of all hotspots (B) Left: TOMTOM DNA Motif analysis of CENP-A hotspots in SW480 and HeLa cells. Right: Pie charts showing similarity of identified hotspots to known classes of transcription factor binding sites. Detailed data for analysis of hotspots can be found in Table 5. Additional file1 contains the full list of hotspots, and a genome-wide overview is in Figure 7. (C) A list of other TOMTOM consensus motifs that correlate to the motifs identified in CENP-A hotspots includes chromatin effector proteins.

Bottom Line: To investigate native CENP-A overexpression, we sought to uncover CENP-A-associated defects in human cells.A distinct class of CENP-A hotspots also accumulates at subtelomeric chromosomal locations, including at the 8q24/Myc region long-associated with genomic instability.These findings suggest that ectopic CENP-A nucleosomes could alter the state of the chromatin fiber, potentially impacting gene regulation and chromosome fragility.

View Article: PubMed Central - PubMed

Affiliation: Chromatin Structure and Epigenetics Mechanisms Unit, Center for Cancer Research, National Cancer Institute National Institutes of Health, 41 Center Drive, Bethesda, MD 20892 USA ; Laboratory of Receptor Biology and Gene Expression, Center for Cancer Research, National Cancer Institute National Institutes of Health, 41 Center Drive, Bethesda, MD 20892 USA.

ABSTRACT

Background: The histone H3 variant CENP-A is normally tightly regulated to ensure only one centromere exists per chromosome. Native CENP-A is often found overexpressed in human cancer cells and a range of human tumors. Consequently, CENP-A misregulation is thought to contribute to genome instability in human cancers. However, the consequences of such overexpression have not been directly elucidated in human cancer cells.

Results: To investigate native CENP-A overexpression, we sought to uncover CENP-A-associated defects in human cells. We confirm that CENP-A is innately overexpressed in several colorectal cancer cell lines. In such cells, we report that a subset of structurally distinct CENP-A-containing nucleosomes associate with canonical histone H3, and with the transcription-coupled chaperones ATRX and DAXX. Furthermore, such hybrid CENP-A nucleosomes localize to DNase I hypersensitive and transcription factor binding sites, including at promoters of genes across the human genome. A distinct class of CENP-A hotspots also accumulates at subtelomeric chromosomal locations, including at the 8q24/Myc region long-associated with genomic instability. We show this 8q24 accumulation of CENP-A can also be seen in early stage primary colorectal tumors.

Conclusions: Our data demonstrate that excess CENP-A accumulates at noncentromeric locations in the human cancer genome. These findings suggest that ectopic CENP-A nucleosomes could alter the state of the chromatin fiber, potentially impacting gene regulation and chromosome fragility.

No MeSH data available.


Related in: MedlinePlus