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Regulation of clustered gene expression by cofactor of BRCA1 (COBRA1) in breast cancer cells

Oncogene volume 26, pages 2543–2553 (2007)Cite this article

Abstract

Eucaryotic genes that are coordinately expressed tend to be clustered. Furthermore, gene clusters across chromosomal regions are often upregulated in various tumors. However, relatively little is known about how gene clusters are coordinately expressed in physiological or pathological conditions. Cofactor of BRCA1 (COBRA1), a subunit of the human negative elongation factor, has been shown to repress estrogen-stimulated transcription of trefoil factor 1 (TFF1 or pS2) by stalling RNA polymerase II. Here, we carried out a genome-wide study to identify additional physiological target genes of COBRA1 in breast cancer cells. The study identified a total of 134 genes that were either activated or repressed upon small hairpin RNA-mediated reduction of COBRA1. Interestingly, many COBRA1-regulated genes reside as clusters on the chromosomes and have been previously implicated in cancer development. Detailed examination of two such clusters on chromosome 21 (21q22) and chromosome X (Xp11) reveals that COBRA1 is physically associated with a subset of its regulated genes in each cluster. In addition, COBRA1 was shown to regulate both estrogen-dependent and -independent transcription of the gene cluster at 21q22, which encompasses the previously identified COBRA1-regulated TFF1 (pS2) locus. Thus, COBRA1 plays a critical role in the regulation of clustered gene expression at preferred chromosomal domains in breast cancer cells.

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Acknowledgements

We thank Asma Amleh and Jianlong Sun for critical reading of the paper, and Yongde Bao for the microarray analysis. The work was supported by a postdoctoral fellowship from DOD. Breast Cancer Research Program to SEA (BC031441), a Cancer Training Grant to ALB and an NIH grant to RL (DK064604).

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  1. S E Aiyar and A L Blair: These authors contributed equally to this work.

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  1. Department of Biochemistry and Molecular Genetics, School of Medicine, University of Virginia, Charlottesville, VA, USA

    S E Aiyar, A L Blair, D A Hopkinson, S Bekiranov & R Li

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  1. S E Aiyar
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Correspondence to R Li.

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Aiyar, S., Blair, A., Hopkinson, D. et al. Regulation of clustered gene expression by cofactor of BRCA1 (COBRA1) in breast cancer cells. Oncogene 26, 2543–2553 (2007). https://doi.org/10.1038/sj.onc.1210047

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