ChIP sequencing of cyclin D1 reveals a transcriptional role in chromosomal instability in mice

Mathew C. Casimiro, Marco Crosariol, Emanuele Loro, Adam Ertel, Zuoren Yu, William Dampier, Elizabeth A. Saria, Alex Papanikolaou, Timothy J. Stanek, Zhiping Li, Chenguang Wang, Paolo Fortina, Sankar Addya, Aydin Tozeren, Erik S. Knudsen, Andrew Arnold, Richard G. Pestell

Research output: Contribution to journalArticle

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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 DNAbound 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.

Original languageEnglish (US)
Pages (from-to)833-843
Number of pages11
JournalJournal of Clinical Investigation
Volume122
Issue number3
DOIs
StatePublished - Mar 1 2012

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Chromosomal Instability
Cyclin D1
Nucleic Acid Regulatory Sequences
Chromosome Aberrations
Transgenic Mice
Spectral Karyotyping
Breast Neoplasms
Gene Expression
Neoplasms
Centrosome
Aneuploidy
Organelle Biogenesis
Human Mammary Glands
Regulator Genes
DNA Sequence Analysis
Transcriptome
Genes
Fluorescent Antibody Technique
Carcinogenesis
Fibroblasts

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Casimiro, M. C., Crosariol, M., Loro, E., Ertel, A., Yu, Z., Dampier, W., ... Pestell, R. G. (2012). ChIP sequencing of cyclin D1 reveals a transcriptional role in chromosomal instability in mice. Journal of Clinical Investigation, 122(3), 833-843. https://doi.org/10.1172/JCI60256

ChIP sequencing of cyclin D1 reveals a transcriptional role in chromosomal instability in mice. / Casimiro, Mathew C.; Crosariol, Marco; Loro, Emanuele; Ertel, Adam; Yu, Zuoren; Dampier, William; Saria, Elizabeth A.; Papanikolaou, Alex; Stanek, Timothy J.; Li, Zhiping; Wang, Chenguang; Fortina, Paolo; Addya, Sankar; Tozeren, Aydin; Knudsen, Erik S.; Arnold, Andrew; Pestell, Richard G.

In: Journal of Clinical Investigation, Vol. 122, No. 3, 01.03.2012, p. 833-843.

Research output: Contribution to journalArticle

Casimiro, MC, Crosariol, M, Loro, E, Ertel, A, Yu, Z, Dampier, W, Saria, EA, Papanikolaou, A, Stanek, TJ, Li, Z, Wang, C, Fortina, P, Addya, S, Tozeren, A, Knudsen, ES, Arnold, A & Pestell, RG 2012, 'ChIP sequencing of cyclin D1 reveals a transcriptional role in chromosomal instability in mice', Journal of Clinical Investigation, vol. 122, no. 3, pp. 833-843. https://doi.org/10.1172/JCI60256
Casimiro, Mathew C. ; Crosariol, Marco ; Loro, Emanuele ; Ertel, Adam ; Yu, Zuoren ; Dampier, William ; Saria, Elizabeth A. ; Papanikolaou, Alex ; Stanek, Timothy J. ; Li, Zhiping ; Wang, Chenguang ; Fortina, Paolo ; Addya, Sankar ; Tozeren, Aydin ; Knudsen, Erik S. ; Arnold, Andrew ; Pestell, Richard G. / ChIP sequencing of cyclin D1 reveals a transcriptional role in chromosomal instability in mice. In: Journal of Clinical Investigation. 2012 ; Vol. 122, No. 3. pp. 833-843.
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AU - Yu, Zuoren

AU - Dampier, William

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AU - Addya, Sankar

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