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

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.

• Authors: Rajbir K Athwal, Marcin P Walkiewicz, Songjoon Baek, Song Fu, Minh Bui, Jordi Camps, Thomas Ried, Myong-Hee Sung, Yamini Dalal
• Journal: Epigenetics & chromatin (Epigenetics Chromatin) Vol. 8 Pg. 2 ( 2015) ISSN: 1756-8935 [Print] England
• PMID: 25788983 (Publication Type: Journal Article)