ChIP sequencing of cyclin D1 reveals a transcriptional role in chromosomal instability in mice.
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.
Department of Cancer Biology, Thomas Jefferson University and Hospital, Kimmel Cancer Center, Philadelphia, Pennsylvania 19107, USA.
Mathew C
MC
Casimiro
Marco
M
Crosariol
Emanuele
E
Loro
Adam
A
Ertel
Zuoren
Z
Yu
William
W
Dampier
Elizabeth A
EA
Saria
Alex
A
Papanikolaou
Timothy J
TJ
Stanek
Zhiping
Z
Li
Chenguang
C
Wang
Paolo
P
Fortina
Sankar
S
Addya
Aydin
A
Tozeren
Erik S
ES
Knudsen
Andrew
A
Arnold
Richard G
RG
Pestell
D000818:Animals; D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D043171:Chromosomal Instability; D002869:Chromosome Aberrations; D019938:Cyclin D1 / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D055106:Genome-Wide Association Study; D006801:Humans; D007621:Karyotyping; D051379:Mice; D008822:Mice, Transgenic; D014158:Transcription, Genetic
D019938:Cyclin D1