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Molecular and Cellular Biology, November 2006, p. 7929-7941, Vol. 26, No. 21
0270-7306/06/$08.00+0     doi:10.1128/MCB.00617-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Role of Topoisomerase IIß in the Expression of Developmentally Regulated Genes{triangledown} ,{dagger}

Yi Lisa Lyu,1* Chao-Po Lin,1 Anna M. Azarova,1 Li Cai,2 James C. Wang,3 and Leroy F. Liu1*

Department of Pharmacology, UMDNJ—Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, New Jersey 08854,1 Department of Biomedical Engineering, Rutgers University, 617 Bowser Road, Piscataway, New Jersey 08854,2 Department of Molecular and Cellular Biology, Harvard University, 7 Divinity Avenue, Cambridge, Massachusetts 021383

Received 10 April 2006/ Returned for modification 18 May 2006/ Accepted 8 August 2006

Mice lacking topoisomerase IIß (TopIIß) are known to exhibit a perinatal death phenotype. In the current study, transcription profiles of the brains of wild-type and top2ß knockout mouse embryos were generated. Surprisingly, only a small number (1 to 4%) of genes were affected in top2ß knockout embryos. However, the expression of nearly 30% of developmentally regulated genes was either up- or down-regulated. By contrast, the expression of genes encoding general cell growth functions and early differentiation markers was not affected, suggesting that TopIIß is not required for early differentiation programming but is specifically required for the expression of developmentally regulated genes at later stages of differentiation. Consistent with this notion, immunohistochemical analysis of brain sections showed that TopIIß and histone deacetylase 2, a known TopIIß-interacting protein, were preferentially expressed in neurons which are in their later stages of differentiation. Chromatin immunoprecipitation analysis of the developing brains revealed TopIIß binding to the 5' region of a number of TopIIß-sensitive genes. Further studies of a TopIIß-sensitive gene, Kcnd2, revealed the presence of TopIIß in the transcription unit with major binding near the promoter region. Together, these results support a role of TopIIß in activation/repression of developmentally regulated genes at late stages of neuronal differentiation.

* Corresponding author. Mailing address: Department of Pharmacology, UMDNJ—Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854. Phone: (732) 235-4592. Fax: (732) 235-4073. E-mail for Leroy F. Liu: lliu{at}umdnj.edu. E-mail for Yi Lisa Lyu: lyuyi{at}umdnj.edu.

{triangledown} Published ahead of print on 21 August 2006.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, November 2006, p. 7929-7941, Vol. 26, No. 21
0270-7306/06/$08.00+0     doi:10.1128/MCB.00617-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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