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Science 22 August 2008:
Vol. 321. no. 5892, pp. 1086 - 1088
DOI: 10.1126/science.1155546
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Reports

Epigenetic Reprogramming by Adenovirus e1a

Roberto Ferrari,1 Matteo Pellegrini,2 Gregory A. Horwitz,3 Wei Xie,1 Arnold J. Berk,3,4 Siavash K. Kurdistani1,5,6*

Adenovirus e1a induces quiescent human cells to replicate. We found that e1a causes global relocalization of the RB (retinoblastoma) proteins (RB, p130, and p107) and p300/CBP histone acetyltransferases on promoters, the effect of which is to restrict the acetylation of histone 3 lysine-18 (H3K18ac) to a limited set of genes, thereby stimulating cell cycling and inhibiting antiviral responses and cellular differentiation. Soon after expression, e1a binds transiently to promoters of cell cycle and growth genes, causing enrichment of p300/CBP, PCAF (p300/CBP-associated factor), and H3K18ac; depletion of RB proteins; and transcriptional activation. e1a also associates transiently with promoters of antiviral genes, causing enrichment for RB, p130, and H4K16ac; increased nucleosome density; and transcriptional repression. At later times, e1a and p107 bind mainly to promoters of development and differentiation genes, repressing transcription. The temporal order of e1a binding requires its interactions with p300/CBP and RB proteins. Our data uncover a defined epigenetic reprogramming leading to cellular transformation.

1 Department of Biological Chemistry, University of California, Los Angeles, CA 90095, USA.
2 Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, CA 90095, USA.
3 Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA.
4 Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095, USA.
5 Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095, USA.
6 Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.

* To whom correspondence should be addressed. E-mail: skurdistani{at}mednet.ucla.edu

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THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Adenovirus Small e1a Alters Global Patterns of Histone Modification.
G. A. Horwitz, K. Zhang, M. A. McBrian, M. Grunstein, S. K. Kurdistani, and A. J. Berk (2008)
Science 321, 1084-1085
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Science. ISSN 0036-8075 (print), 1095-9203 (online)