Content area
Full text
Identification of branched-chain amino acid (BCAA) oxidation enzymes in the nucleus led us to predict that they are a source of the propionyl-CoA that is utilized for histone propionylation and, thereby, regulate gene expression. To investigate the effects of BCAAs 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 BCAAs (BCAA control) versus a BCAA-free diet. The former was associated with an increase in histone H3K23-propionyl (H3K23Pr) at the promoters of upregulated genes (e.g., cell signaling and extracellular matrix genes) and a decrease at the promoters of downregulated genes (e.g., electron transfer complex [ETC l-V] and metabolic genes). I nt rigu ingly, the BCAA-free diet tempered the increases in promoter H3K23Pr, thus reducing collagen gene expression and fibrosis during cardiac hypertrophy. Conversely, the BCAA-free diet inhibited the reductions in promoter H3K23Pr and abolished the down regulation of ETC l-V subunits, enhanced mitochondrial respiration, and curbed the progression of cardiac hypertrophy. Thus, lowering the intake of BCAAs reduced pressure overload-induced changes in histone propionylation-dependent gene expression in the heart, which retarded the development of cardiomyopathy.
Introduction
Transcriptional homeostasis is fundamental to our health and adaptability, as its disruption underlies the pathogenesis of a broad range of diseases. The codes that regulate transcriptional initiation, pausing, the elongation rate, silencing, or memory are written by a highly intricate set of histone posttranslational modifications that have yet to be fully deciphered. To put this in perspective, histone H3 has 13 Lys residues, with 11 known modifiers so far (1), potentially resulting in over 34 x 109 permutations of modified H3. In general, studies have focused on histone acetylation and methylation as modifiers of a gene's transcriptional activity since they were the first discovered and are highly abundant. During the past decade, however, more modifiers have been identified by mass spectrometry, including several short-chain fatty acid (SCFA) modifications (1), such as propionylation, butyrylation, and crotonylation, whose role in gene expression remain to be investigated.
We recently identified branched-chain amino acid (BCAA) oxidation enzymes in both human and rodent nuclei (2), which suggested that they may be a source of localized propionyl-CoA that can be utilized for histone modification, particularly since CoA metabolic...