The effect of a BCCA-free diet on 2W pressure overload-induced H3K23-propionyl [BCAA-free-2W-TAC-ChIP-Seq]
Identifying branched-chain amino acid (BCAA) oxidation enzymes in the nucleus led us to predict that they are a source of propionyl-CoA that could be utilized for histone propionylation and, thereby, regulate gene expression. To investigate this and its effect on the development of cardiac hypertrophy and failure, we applied pressure overload on the heart in mice maintained on a diet with standard levels of BCAA (BCAA-control) versus a BCAA-free diet. The former was associated with an increase in H3K23-propionyl (H3K23Pr) at the promoters of upregulated genes [e.g., cell signaling and extracellular matrix (ECM) genes] and a decrease at the promoters of downregulated genes [e.g., electron transfer complex (ETC I-V) and metabolic genes]. Intriguingly, the BCAA-free diet diminished the increase in promoter-H3K23Pr and significantly reduced ECM gene expression and collagen deposition. Conversely, the BCAA-free diet abolished the downregulation of ETC I-V subunits, enhanced mitochondrial respiration, and curbed cardiac hypertrophy. Thus, lowering the intake of BCAA reduces histone propionylation, which moderates the effects of stress on the heart. Overall design: Mice were fed a BCAA-free diet or a BCAA-control diet for 4 days. Mice were then subjected to a sham or transverse aortic constriction (TAC) surgery for 2-week (2W), while being maintained on the same diets.  The heart function and structure was asssessed by echocardiography, the heart isolated, chromatin extracted and analyzed by ChIP-Seq, each sample is a pool of 3 hearts (Active Motif). The antibody used for the ChIP-seq is anti-H3K23-propionyl (Abcam, ab2414466).