title: 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: 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.
authors: Rajbir K
authors: RK
authors: Athwal
authors: 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.
authors: Marcin P
authors: MP
authors: Walkiewicz
authors: 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.
authors: Songjoon
authors: S
authors: Baek
authors: 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.
authors: Song
authors: S
authors: Fu
authors: 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.
authors: Minh
authors: M
authors: Bui
authors: Genetics Branch, Center for Cancer Research, National Cancer Institute National Institutes of Health, 50 South Drive, Bethesda, MD 20892 USA.
authors: Jordi
authors: J
authors: Camps
authors: Genetics Branch, Center for Cancer Research, National Cancer Institute National Institutes of Health, 50 South Drive, Bethesda, MD 20892 USA.
authors: Thomas
authors: T
authors: Ried
authors: 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.
authors: Myong-Hee
authors: MH
authors: Sung
authors: Chromatin Structure and Epigenetics Mechanisms Unit, Center for Cancer Research, National Cancer Institute National Institutes of Health, 41 Center Drive, Bethesda, MD 20892 USA.
authors: Yamini
authors: Y
authors: Dalal