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Science 22 May 2009:
Vol. 324. no. 5930, pp. 1076 - 1080
DOI: 10.1126/science.1164097
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Reports

ATP-Citrate Lyase Links Cellular Metabolism to Histone Acetylation

Kathryn E. Wellen,* Georgia Hatzivassiliou,*,{dagger} Uma M. Sachdeva, Thi V. Bui, Justin R. Cross, Craig B. Thompson{ddagger}

Histone acetylation in single-cell eukaryotes relies on acetyl coenzyme A (acetyl-CoA) synthetase enzymes that use acetate to produce acetyl-CoA. Metazoans, however, use glucose as their main carbon source and have exposure only to low concentrations of extracellular acetate. We have shown that histone acetylation in mammalian cells is dependent on adenosine triphosphate (ATP)–citrate lyase (ACL), the enzyme that converts glucose-derived citrate into acetyl-CoA. We found that ACL is required for increases in histone acetylation in response to growth factor stimulation and during differentiation, and that glucose availability can affect histone acetylation in an ACL-dependent manner. Together, these findings suggest that ACL activity is required to link growth factor–induced increases in nutrient metabolism to the regulation of histone acetylation and gene expression.

Department of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.

* These authors contributed equally to this work.

{dagger} Present address: Genentech Inc., South San Francisco, CA 94080, USA.

{ddagger} To whom correspondence should be addressed. E-mail: craig{at}mail.med.upenn.edu

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