Propionyl-CoA metabolism links chromatin acylation to cardiac transcription

Abstract

The molecular mechanisms that link propionyl-CoA metabolism and epigenetic regulation of gene expression are unclear, as are the implications for heart function. Now, new insights into the modulation of chromatin acylation and transcription by aberrant oxidation of propionyl-CoA are revealed in the dysfunctional hearts of mice with propionic acidemia.

Metabolic pathways are required for the transformation of cellular energy, for the conversion of biomass, and for the generation of substrates for cell signaling processes. For instance, the availability of certain substrates influences post-translational modifications of chromatin, creating a bidirectional link between metabolism and epigenetics¹. Established examples of such metabolites are acetyl-CoA and S-adenosylmethionine — the substrates for histone acetylation and methylation, respectively. Less well known are the molecular mechanisms that link the metabolite propionyl-CoA (pr-CoA) to propionylation, or the interdependence of different acylations that require a shared CoA cofactor². The implications of metabolite-dependent epigenetic modifications in heart disease also remain unclear, despite growing evidence that cardiac metabolism and epigenetics are targetable in specific cardiac pathologies. In this issue of Nature Cardiovascular Research, Park et al.³ investigate abnormal pr-CoA metabolism in a mouse model of heart disease, uncovering several connections between chromatin acylation, transcription, and cardiac dysfunction.

Pr-CoA can be synthesized from propiogenic nutrients that include odd-chain fatty acids, cholesterol, and the branched-chain amino acids valine and isoleucine. Pr-CoA is catabolized via propionyl-CoA carboxylase to d- and then l-methylmalonyl-CoA, which in mitochondria contributes four carbons to the tricarboxylic acid (TCA) cycle as succinyl-CoA⁴. An alternative fate for pr-CoA is for the propionyl group to serve as an acyl donor for the propionylation of histone lysine residues — a post-translational modification (PTM) on the ε-amino group of a lysine side chain that is associated with chromatin decompaction and gene activation^5,6. Compared with histone acetylation, the distinct regulatory function of histone propionylation is not well understood². Alternatively, pr-CoA can be interconverted with propionate, a short-chain fatty acid that has been suggested to impede the activity of histone deacetylase⁷.

A failure of pr-CoA oxidation, resulting from a wide variety of loss-of-function mutations in the propionyl-CoA carboxylase (encoded by the genes PCCA and PCCB), leads to the development of an inborn error of metabolism known as propionic acidemia (Online Mendelian Inheritance in Man (OMIM) accession number 606054). This disorder is characterized pathologically by multiorgan dysfunction with mitochondrial complications and the accumulation of metabolites that would normally be catabolized via pr-CoA⁸. This dysregulation can be diagnosed in newborns through screening for elevated levels of metabolites such as propionylcarnitine and 2-methylcitrate. Individuals with propionic acidemia — even those with a mild disease or those who avoid metabolic decompensation — are susceptible to developing cardiac disorders, including dilated cardiomyopathy and long-QT arrythmias, which can be fatal⁹. Heart disease related to propionic acidemia has been linked to mitochondrial dysfunction and impaired myocardial energetics. However, the roles of metabolic remodeling of pr-CoA in the epigenetic regulation of cardiac gene expression remain unclear.

Park et al.³ used a mouse model of a pathologically ‘mild’ form of propionic acidemia, with genetically defective propionyl-CoA carboxylase activity, to investigate the interplay between altered cardiac pr-CoA metabolism and transcription (Fig. 1). Examining the metabolomes of blood, liver, and cardiac tissue, the authors found that the common metabolic alterations seen in the bloodstream and liver were reflected in cardiac tissue. These included marked accumulation of pr-CoA and its downstream metabolites 2-methylcitrate, propionylcarnitine, and propionyl-glycine.

Fig. 1 |. A role for pr-CoA in cardiac transcription and health.

Park et al.³ have used a mouse model of mild propionic acidemia, involving genetic defects in propionyl-CoA carboxylase, to investigate the interplay between cardiac pr-CoA metabolism and transcription. a, Cells can use pr-CoA to propionylate histone lysines, influencing transcription; in proprionic acidemia, changes in pr-CoA metabolism lead, via changes in transcription, to cardiac remodeling. b, Using the mouse model, Park et al. show an increase in pr-CoA abundance in mutant cardiomyocytes, resulting in reduced activity of the TCA cycle and enhanced histone propionylation and acetylation specifically at promoter regions of active genes (such as Pde9a and Mme). This leads to increased signaling via cGMP, affecting contractile function. β-Alanine inhibits the accumulation of pr-CoA. c, Notably, Park et al.³ found that only female mice exhibited decreased cardiac function; females also showed higher pr-CoA levels, more post-translational modifications, and more substantial maladaptive transcriptional remodeling when compared with male mice, probably because of lower β-alanine levels.

One particularly interesting finding was that female hearts accumulated more pr-CoA metabolites than male hearts. The accumulation of β-alanine in male hearts, which was not observed in females, correlated with a decreased accumulation of pr-CoA metabolites, suggesting a role for β-alanine in propionic acidemia. To corroborate the association between β-alanine and pr-CoA in vitro, the researchers cultured ventricular myocytes in propionate-rich medium in which histidine was substituted with carnosine to increase intracellular β-alanine levels. They found that the higher β-alanine levels seen in priopionate-challenged myocytes were linked to reduced pr-CoA pools, and were accompanied by a partial rescue of intermediates of the TCA cycle, suggesting restored mitochondrial function in myocytes and cardiac protection. On the other hand, the more substantial cardiac metabolic defect seen in females with propionic acidemia correlated with modest contractile dysfunction, indicated by a reduction in the ejection fraction. In the future, examination of sex-dependent variations in pr-CoA metabolism may provide useful clinical insights into the natural history of propionic acidemia, with implications for screening in infancy or for decompensation later in life.

The authors next investigated whether cardiac transcriptional patterns are influenced by the reprogramming in pr-CoA metabolism that is evoked by propionic acidemia. Consistent with the alterations in metabolite levels, the hearts of female mice with propionic acidemia showed a substantially higher number of differentially expressed genes than did their healthy littermates. The authors then cross-referenced the differentially expressed genes with in vitro RNA-sequencing (RNA-seq) profiles from cultured ventricular myocytes treated with a supraphysiological concentration of sodium propionate. Through a series of rigorous measurements, they showed that the in vitro experiments did in fact correspond to the biological range of propionate in their model. This analysis revealed transcriptional signatures implicated in tyrosine metabolism and xenobiotic metabolism by P450 as possible direct targets of pr-CoA/propionate metabolism, while different genes involved with diastolic dysfunction, such as Pde9a, were upregulated only in female hearts. Some caution here is warranted, as correlations between RNA-seq and proteomics measurements can vary substantially across metabolic gene ontologies¹⁰. Nevertheless, these results prompt the question: how does the abnormal accumulation of pr-CoA and propionate regulate cardiac transcription?

Park et al.³ speculated that the gene-expression signature seen in hearts with propionic acidemia might be attributed to differences in chromatin propionylation. Isotope-tracing experiments in isolated myocytes revealed that histone propionylation originates both in pr-CoA from branched-chain amino acids and in propionate, consistent with prior work⁶. Intriguingly, a high propionate availability promotes the labeling of histones H3K14 and H3K23 specifically, suggesting that pr-CoA metabolism could elicit a transcriptional response through site-specific histone propionylation. Propionate has been suggested to have a dual role in gene expression, by providing the propionyl moiety for lysine propionylation and by acting as a histone deacetylase inhibitor to stimulate lysine acetylation⁷, although the latter is less well defined. Of note, the authors show that global histone lysine propionylation and acetylation are both increased in the promoters of active genes in hearts with propionate acidemia.

They also found that, in contrast with males, female hearts displayed enhanced acetyl occupancy of H3K27 in the promoters of propionate-dependent genes, such as Pde9a. This is an exciting finding, as propionylated H3K23 on gene promoters has been independently implicated in cardiomyopathy, as a chromatin acylation mark responsive to the availability of propiogenic branched-chain amino acids¹¹. Therefore, accumulation of pr-CoA/propionate influences the deposition of chromatin acylation marks, partly through pr-CoA-deposited propionylation and, indirectly, through acetylation, potentially driving gene programs that promote contractile dysfunction in female mice with propionyl acidemia.

The findings of Park et al.³ raise both fundamental and applied questions for the future. First, the authors have focused on genes that are regulated by the combined functions of propionylation and acetylation. However, some genes are affected solely by changes in histone propionylation, raising the interesting possibility that different acylation marks could have distinct functional properties. Hence, assessing the regulation of this subset of genes may unravel the unique and as-yet-unknown roles of histone propionylation in the context of cardiac pr-CoA metabolism. Furthermore, the targeting of histone PTMs may offer a possible route to the treatment of individuals with inborn errors of metabolism and cardiac pathologies. Second, the researchers used an unbiased phosphoproteomic approach in their attempt to understand how, in mice with propionic acidemia, cardiac dysregulation of pr-CoA metabolism drives a sex-dependent contractile phenotype through changes in histone acylation and gene expression. Although the authors observed some differences in the heart phosphoproteome, mechanistically it is unclear how these epigenetic and transcriptional changes promote the development of cardiac disease.

In summary, Park et al.³ have defined the importance of reprogrammed pr-CoA metabolism in driving chromatin acylation and transcription in the context of heart disease in propionic acidemia. This study provides a foundation for work that will target this process and elucidate the broader role of increased pr-CoA/propionate metabolism in driving cardiovascular-associated diseases, such as cardiac hypertrophy and failure, through changes in histone PTMs.