Myc-dependent Mitochondrial Generation of Acetyl-CoA Contributes to Fatty Acid Biosynthesis and Histone Acetylation during Cell Cycle Entry |
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Authors: | Fionnuala Morrish Jhoanna Noonan Carissa Perez-Olsen Philip R. Gafken Matthew Fitzgibbon Joanne Kelleher Marc VanGilst David Hockenbery |
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Affiliation: | From the ‡Fred Hutchinson Cancer Research Center, Seattle, Washington 98109.;the §Molecular and Cellular Biology Program, University of Washington, Seattle, Washington 98109, and ;the ¶Department of Chemical Engineering, Massachusetts Institute of Technology, Boston, Massachusetts 02139 |
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Abstract: | Cell reprogramming from a quiescent to proliferative state requires coordinate activation of multiple -omic networks. These networks activate histones, increase cellular bioenergetics and the synthesis of macromolecules required for cell proliferation. However, mechanisms that coordinate the regulation of these interconnected networks are not fully understood. The oncogene c-Myc (Myc) activates cellular metabolism and global chromatin remodeling. Here we tested for an interconnection between Myc regulation of metabolism and acetylation of histones. Using [13C6]glucose and a combination of GC/MS and LC/ESI tandem mass spectrometry, we determined the fractional incorporation of 13C-labeled 2-carbon fragments into the fatty acid palmitate, and acetyl-lysines at the N-terminal tail of histone H4 in myc−/− and myc+/+ Rat1A fibroblasts. Our data demonstrate that Myc increases mitochondrial synthesis of acetyl-CoA, as the de novo synthesis of 13C-labeled palmitate was increased 2-fold in Myc-expressing cells. Additionally, Myc induced a forty percent increase in 13C-labeled acetyl-CoA on H4-K16. This is linked to the capacity of Myc to increase mitochondrial production of acetyl-CoA, as we show that mitochondria provide 50% of the acetyl groups on H4-K16. These data point to a key role for Myc in directing the interconnection of -omic networks, and in particular, epigenetic modification of proteins in response to proliferative signals. |
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Keywords: | Acetyl-Coenzyme A Histone Modification Isotopic Tracers Lipid Synthesis Mitochondrial Metabolism |
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