Doctor of Philosophy
Dr. Yuhai Cui
Dr. Susanne Kohalmi
Acetyl-coenzyme A (acetyl-CoA) serves as a central metabolite in energy metabolism and biosynthesis. High level of acetyl-CoA can fuel the tricarboxylic acid (TCA) cycle to generate energy and store excess energy in fatty acids. Meanwhile, it also provides acetyl groups for protein acetylation, which normally occurs at the lysine or arginine residues. Acetylation regulates protein functions largely due to the change of total charges. Acetylation of histones, for example, can lead to loss of the interaction between histone and DNA, thus relaxing chromatin structure and potentially promoting gene expression. However, whether and how acetyl-CoA regulates plant chromatin remains unexplored. Here, I show that dysfunction of cytosolic acetyl-CoA carboxylase 1 (ACC1), a key enzyme for catalyzing the carboxylation of acetyl-CoA to malonyl-CoA, leads to elevated levels of acetyl-CoA and promotes histone acetylation in Arabidopsis. The increased accumulation of acetyl-CoA is also dependent on the activity of ATP-citrate lyase, a cytosolic enzyme which can generate cytosolic acetyl-CoA from citrate. In the wave of high levels of acetyl-CoA, hyperacetylation is mainly detected at lysine 27 of histone H3 (H3K27). Using a pharmacological approach, I demonstrate that this increase of H3K27 acetylation (H3K27ac) is dependent on the activity of histone acetyltransferase. Further, by generating and analyzing double mutants of acc1 and mutants of each of the histone acetyltransferases, I found that General Control Non-depressible 5 (GCN5), a histone acetyltransferase of the GNAT family, is necessary for the increased H3K27ac in acc1. Consistently, the morphological phenotype of acc1 can be partially rescued by knocking out GCN5 and the H3K27ac levels in the double mutant (gcn5 acc1) are restored to WT levels at several selected genes. Finally, transcriptome analysis shows that increased H3K27ac in acc1 can significantly promote transcription. Altogether, this study reveals that acetylation at H3K27 may be an important link between cytosolic acetyl-CoA level and gene expression in response to changes of the metabolic environments in plants.
Chen, Chen, "Cytosolic acetyl-CoA promotes histone H3 lysine 27 acetylation in Arabidopsis" (2017). Electronic Thesis and Dissertation Repository. 4423.
Available for download on Monday, January 01, 2018