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首页> 外文期刊>Epigenetics & Chromatin >CENP-A nucleosomes localize to transcription factor hotspots and subtelomeric sites in human cancer cells
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CENP-A nucleosomes localize to transcription factor hotspots and subtelomeric sites in human cancer cells

机译：CENP-A核小体定位于人类癌细胞中的转录因子热点和亚端粒位点

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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.
机译：背景技术组蛋白H3变异体CENP-A通常受到严格调节，以确保每个染色体仅存在一个着丝粒。天然CENP-A通常在人类癌细胞和一系列人类肿瘤中过表达。因此，CENP-A的失调被认为是导致人类癌症中基因组不稳定的原因。但是，尚未在人癌细胞中直接阐明这种过度表达的后果。结果为了研究天然CENP-A的过表达，我们试图揭示人类细胞中CENP-A相关的缺陷。我们证实CENP-A在几种结直肠癌细胞系中天生过表达。在此类细胞中，我们报道了结构不同的含CENP-A的核小体的一个子集与规范组蛋白H3以及与转录偶联的分子伴侣ATRX和DAXX相关联。此外，此类杂化CENP-A核小体位于DNase I超敏和转录因子结合位点，包括在整个人类基因组的基因启动子处。 CENP-A热点的独特类别也聚集在亚端粒染色体位置，包括与基因组不稳定长期相关的8q24 / Myc区。我们显示CENP-A的这种8q24积累也可以在早期原发性大​​肠肿瘤中看到。结论我们的数据表明，过量的CENP-A会积聚在人类癌症基因组的非着丝粒位置。这些发现表明，异位CENP-A核小体可能会改变染色质纤维的状态，从而可能影响基因调控和染色体脆性。

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