Journal article
ChIP sequencing of cyclin D1 reveals a transcriptional role in chromosomal instability in mice
The Journal of clinical investigation, v 122(3), pp 833-843
01 Mar 2012
PMID: 22307325
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Chromosomal instability (CIN) in tumors is characterized by chromosomal abnormalities and an altered gene expression signature; however, the mechanism of CIN is poorly understood.
CCND1
(which encodes cyclin D1) is overexpressed in human malignancies and has been shown to play a direct role in transcriptional regulation. Here, we used genome-wide ChIP sequencing and found that the DNA-bound form of cyclin D1 occupied the regulatory region of genes governing chromosomal integrity and mitochondrial biogenesis. Adding cyclin D1 back to
Ccnd1
–/–
mouse embryonic fibroblasts resulted in CIN gene regulatory region occupancy by the DNA-bound form of cyclin D1 and induction of CIN gene expression. Furthermore, increased chromosomal aberrations, aneuploidy, and centrosome abnormalities were observed in the cyclin D1–rescued cells by spectral karyotyping and immunofluorescence. To assess cyclin D1 effects in vivo, we generated transgenic mice with acute and continuous mammary gland–targeted cyclin D1 expression. These transgenic mice presented with increased tumor prevalence and signature CIN gene profiles. Additionally, interrogation of gene expression from 2,254 human breast tumors revealed that cyclin D1 expression correlated with CIN in luminal B breast cancer. These data suggest that cyclin D1 contributes to CIN and tumorigenesis by directly regulating a transcriptional program that governs chromosomal stability.
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Details
- Title
- ChIP sequencing of cyclin D1 reveals a transcriptional role in chromosomal instability in mice
- Creators
- Mathew C Casimiro - Department of Cancer Biology, Thomas Jefferson University and Hospital, Kimmel Cancer Center, Philadelphia, Pennsylvania, USAMarco Crosariol - Department of Cancer Biology, Thomas Jefferson University and Hospital, Kimmel Cancer Center, Philadelphia, Pennsylvania, USAEmanuele Loro - Department of Cancer Biology, Thomas Jefferson University and Hospital, Kimmel Cancer Center, Philadelphia, Pennsylvania, USAAdam Ertel - Department of Cancer Biology, Thomas Jefferson University and Hospital, Kimmel Cancer Center, Philadelphia, Pennsylvania, USAZuoren Yu - Department of Cancer Biology, Thomas Jefferson University and Hospital, Kimmel Cancer Center, Philadelphia, Pennsylvania, USAWilliam Dampier - Department of Cancer Biology, Thomas Jefferson University and Hospital, Kimmel Cancer Center, Philadelphia, Pennsylvania, USAElizabeth A Saria - Department of Cancer Biology, Thomas Jefferson University and Hospital, Kimmel Cancer Center, Philadelphia, Pennsylvania, USAAlex Papanikolaou - Department of Cancer Biology, Thomas Jefferson University and Hospital, Kimmel Cancer Center, Philadelphia, Pennsylvania, USATimothy J Stanek - Department of Cancer Biology, Thomas Jefferson University and Hospital, Kimmel Cancer Center, Philadelphia, Pennsylvania, USAZhiping Li - Department of Cancer Biology, Thomas Jefferson University and Hospital, Kimmel Cancer Center, Philadelphia, Pennsylvania, USAChenguang Wang - Department of Cancer Biology, Thomas Jefferson University and Hospital, Kimmel Cancer Center, Philadelphia, Pennsylvania, USAPaolo Fortina - Department of Cancer Biology, Thomas Jefferson University and Hospital, Kimmel Cancer Center, Philadelphia, Pennsylvania, USASankar Addya - Department of Cancer Biology, Thomas Jefferson University and Hospital, Kimmel Cancer Center, Philadelphia, Pennsylvania, USAAydin Tozeren - Department of Cancer Biology, Thomas Jefferson University and Hospital, Kimmel Cancer Center, Philadelphia, Pennsylvania, USAErik S Knudsen - Department of Cancer Biology, Thomas Jefferson University and Hospital, Kimmel Cancer Center, Philadelphia, Pennsylvania, USAAndrew Arnold - Department of Cancer Biology, Thomas Jefferson University and Hospital, Kimmel Cancer Center, Philadelphia, Pennsylvania, USARichard G Pestell - Department of Cancer Biology, Thomas Jefferson University and Hospital, Kimmel Cancer Center, Philadelphia, Pennsylvania, USA
- Publication Details
- The Journal of clinical investigation, v 122(3), pp 833-843
- Publisher
- American Society for Clinical Investigation
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology; [Retired Faculty]
- Web of Science ID
- WOS:000301021500011
- Scopus ID
- 2-s2.0-84863256545
- Other Identifier
- 991014877881404721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Medicine, Research & Experimental