ATP-Citrate Lyase Links Cellular Metabolism to Histone Acetylation

Chromatin Modifier Modulates Gene Expression Modification of chromatin structure is usually thought of as a global, relatively nonspecific way of modulating gene expression. However, Wellen et al. (p. 1076; see the Perspective by Rathmell and Newgard) demonstrate that such regulation helps link growth factor–stimulated increases in metabolism to appropriate changes in gene expression. Adenosine triphosphate (ATP)–citrate lyase (ACL), which converts citrate to acetyl–coenzyme A (CoA) in the mitochondria of mammalian cells during metabolism of glucose, was also found to be present in the nucleus, where it might regulate activity of histone acetyl transferases (HATs) by controlling the availability of acetyl-CoA. Indeed, depletion of ACL from cultured human colon carcinoma cells specifically decreased histone acetylation in the nucleus, but appeared not to affect the overall amount of acetylation of proteins in the cells. Loss of ACL in cultured mouse 3T3-L1 cells diminished the increase in histone acetylation normally associated with hormone-stimulated differentiation of these cells and inhibited the increase in expression of specific genes, such as that encoding the Glut4 glucose transporter. Thus, ACL may help cells link metabolic activity to changes in gene expression. Histone acetylation and gene expression in mammals are modulated by glycolytic metabolism. 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.

[1]  L. Tora,et al.  Distinct GCN5/PCAF-containing complexes function as co-activators and are involved in transcription factor and global histone acetylation , 2007, Oncogene.

[2]  AC Tose.  Cell , 1993, Cell.

[3]  These authors contributed equally to this work. , 2007 .

[4]  L. Mahadevan,et al.  Enhanced histone acetylation and transcription: a dynamic perspective. , 2006, Molecular cell.

[5]  R. Treisman,et al.  Activation of SRF-Regulated Chromosomal Templates by Rho-Family GTPases Requires a Signal that Also Induces H4 Hyperacetylation , 1998, Cell.

[6]  C. Allis,et al.  Conservation of deposition-related acetylation sites in newly synthesized histones H3 and H4. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[7]  Philip R. Gafken,et al.  Myc influences global chromatin structure , 2006, The EMBO journal.

[8]  Eric Verdin,et al.  Conserved metabolic regulatory functions of sirtuins. , 2008, Cell metabolism.

[9]  P. Iyengar,et al.  The Hyperglycemia-induced Inflammatory Response in Adipocytes , 2005, Journal of Biological Chemistry.

[10]  J. B. Kim,et al.  Down-regulation of Histone Deacetylases Stimulates Adipocyte Differentiation* , 2006, Journal of Biological Chemistry.

[11]  宁北芳,et al.  疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A , 2005 .

[12]  R. Schneider,et al.  Dynamics and interplay of nuclear architecture, genome organization, and gene expression. , 2007, Genes & development.

[13]  B. Turner,et al.  Essential and redundant functions of histone acetylation revealed by mutation of target lysines and loss of the Gcn5p acetyltransferase , 1998, The EMBO journal.

[14]  D. Sterner,et al.  Acetylation of Histones and Transcription-Related Factors , 2000, Microbiology and Molecular Biology Reviews.

[15]  J. Licht,et al.  Epigenetic regulation of normal and malignant hematopoiesis , 2007, Oncogene.

[16]  B. Puschendorf,et al.  Histone acetylation and histone synthesis in mouse fibroblasts during quiescence and restimulation into S-phase , 1991, Molecular and Cellular Biochemistry.

[17]  A. Johnsson,et al.  Stress-Specific Role of Fission Yeast Gcn5 Histone Acetyltransferase in Programming a Subset of Stress Response Genes , 2006, Eukaryotic Cell.

[18]  R. Rosenfeld.  Nature , 2009, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[19]  Zigang Dong,et al.  Post-translational modification of p53 in tumorigenesis , 2004, Nature Reviews Cancer.

[20]  B. Bainbridge,et al.  Genetics , 1981, Experientia.

[21]  J. Davie,et al.  Effect of Estradiol on Histone Acetylation Dynamics in Human Breast Cancer Cells* , 2001, The Journal of Biological Chemistry.

[22]  Dudley Lamming,et al.  Nutrient-Sensitive Mitochondrial NAD+ Levels Dictate Cell Survival , 2007, Cell.

[23]  Michael Grunstein,et al.  Histone acetylation and deacetylation in yeast , 2003, Nature Reviews Molecular Cell Biology.

[24]  Daniel E Bauer,et al.  ATP citrate lyase inhibition can suppress tumor cell growth. , 2005, Cancer cell.

[25]  Guido Caldarelli,et al.  Scale-Free Networks , 2007 .

[26]  M. Groudine,et al.  Expression of the c-myb proto-oncogene during cellular proliferation , 1986, Nature.

[27]  J. Botto,et al.  The plant cell , 2007, Plant Molecular Biology Reporter.

[28]  R. Cole,et al.  Sir2-Dependent Activation of Acetyl-CoA Synthetase by Deacetylation of Active Lysine , 2002, Science.

[29]  W. C. Hallows,et al.  Sirtuins deacetylate and activate mammalian acetyl-CoA synthetases , 2006, Proceedings of the National Academy of Sciences.

[30]  P. Kaye.  Infectious diseases of humans: Dynamics and control , 1993 .

[31]  Myriam Gorospe,et al.  Calorie Restriction Promotes Mammalian Cell Survival by Inducing the SIRT1 Deacetylase , 2004, Science.

[32]  P. Silver,et al.  Global histone acetylation induces functional genomic reorganization at mammalian nuclear pore complexes. , 2008, Genes & development.

[33]  Bing Li,et al.  The Role of Chromatin during Transcription , 2007, Cell.

[34]  L. C. Moore,et al.  Nuclear envelope permeability , 1975, Nature.

[35]  K. Deisseroth,et al.  Phasic Firing in Dopaminergic Neurons Is Sufficient for Behavioral Conditioning , 2009, Science.

[36]  Z. Herceg,et al.  Histone acetylation and chromatin signature in stem cell identity and cancer. , 2008, Mutation research.

[37]  L. Guarente,et al.  Nicotinamide adenine dinucleotide, a metabolic regulator of transcription, longevity and disease. , 2003, Current opinion in cell biology.

[38]  E. Seto,et al.  Histone deacetylases and cancer , 2007, Oncogene.

[39]  D. Reinberg,et al.  NAD+-dependent deacetylation of H4 lysine 16 by class III HDACs , 2007, Oncogene.

[40]  Rafael A Irizarry,et al.  Nucleocytosolic acetyl-coenzyme a synthetase is required for histone acetylation and global transcription. , 2006, Molecular cell.

[41]  B. Morgan,et al.  Histone H4 and the maintenance of genome integrity. , 1995, Genes & development.