What Enzymes Regulate Histone Propionylation?
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Catalyzes propionylation at sites such as H3K18, H3K23, H4K5, and H4K8.
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Promotes chromatin accessibility and gene activation.
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Classical acetyltransferases that can also utilize propionyl-CoA to catalyze H3 propionylation.
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Frequently cooperate with the SAGA complex to regulate promoter accessibility.
- Primarily targets H4K16, and in vitro studies have demonstrated its ability to catalyze propionylation.
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SIRT1/2/3: NAD⁺-dependent deacylases capable of removing H3/H4 propionylation.
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SIRT5: Particularly responsive to medium- and short-chain acyl modifications, including propionylation and butyrylation.
- Can remove selected HPr sites within the nucleus, although their catalytic efficiency is generally lower than that observed for acetylation.
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Fatty acid β-oxidation (particularly odd-chain fatty acids).
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Degradation of branched-chain amino acids (isoleucine, valine, and methionine).
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Propionic acid generated by gut microbiota.
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Elevated propionyl-CoA → Increased HPr → Activation of metabolism-related genes.
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This indicates that HPr serves as a metabolic state-sensing marker and may be more responsive than acetylation.
Histone propionylation (HPr) is a newly recognized short-chain fatty acid-derived histone modification that plays an important role in regulating chromatin architecture and gene expression. Unlike conventional acetylation, HPr involves the addition of a propionyl group (C3 chain) to lysine residues and can serve as a more sensitive indicator of intracellular metabolic states, particularly dynamic fluctuations in propionyl-CoA. This modification has demonstrated distinct regulatory potential in hepatic metabolism, immune responses, and tumorigenesis. With advances in mass spectrometry, HPr sites and their associated regulatory enzymes can now be characterized with high precision, providing new insights into epigenetic regulation and disease mechanisms.
Overview Of Histone Propionylation
Histone propionylation belongs to the class of short-chain fatty acid modifications (SCFA modifications). Its chemical structure is similar to that of histone acetylation; however, subtle differences exist in chromatin accessibility and charge modulation. HPr is widely regarded as an epigenetic signal reflecting cellular metabolic states, capable of rapidly responding to fluctuations in propionyl-CoA levels and influencing gene transcription, chromatin conformation, and metabolism-associated signaling pathways.
Writers Of Histone Propionylation
The deposition of HPr is mediated by lysine acetyltransferases (KATs), which can utilize propionyl-CoA as an acyl donor to transfer propionyl groups onto histone lysine residues. Major enzymes include:
1. p300/CBP (KAT3A/KAT3B)
2. GCN5/PCAF (KAT2A/KAT2B)
3. MOF (KAT8)
Erasers Of Histone Propionylation
The removal of HPr is primarily mediated by HDACs and members of the Sirtuin family, often in a site-specific manner:
1. Sirtuin Family (SIRT1/2/3/5/6)
2. HDAC1/2/3 (Class I HDACs)
Auxiliary Recognition Proteins (Readers)
The biological functions of histone propionylation depend not only on writers and erasers, but also on downstream recognition proteins (readers). The Bromodomain (BRD) family represents one of the principal recognition modules for HPr. Certain BRD domains can bind propionylated lysine residues, including H3K23Pr, H4K5Pr, and H4K8Pr. This interaction resembles acetyl-lysine recognition; however, binding affinity toward propionylated sites may be slightly reduced, suggesting that cells can differentially interpret distinct short-chain fatty acid-derived modifications.
In addition to the BRD family, YEATS domain-containing proteins (such as AF9 and ENL) have also been shown to recognize H3/H4 propionylation and participate in chromatin remodeling and transcriptional activation. YEATS proteins are enriched at enhancer and promoter regions, where they amplify HPr-mediated regulation of gene expression through recruitment of transcriptional complexes and RNA polymerase II.
Furthermore, certain transcription factors and chromatin-remodeling complexes may indirectly respond to propionylation states. For example, upon recognition of HPr, the SAGA complex and the p300/CBP complex may enhance acetyltransferase activity or recruit additional transcriptional co-factors, thereby coordinating chromatin accessibility and gene activation.
Relationship Between Metabolism And Histone Propionylation
1. Sources Of Propionyl-CoA Donors
2. Regulatory Logic
HPr Regulatory Enzyme Network
Histone propionylation is installed by writer enzymes such as p300/CBP and GCN5/PCAF, removed by members of the Sirtuin and HDAC families, and recognized by BRD family proteins to regulate gene expression. Beyond serving as a component of epigenetic regulation, it also acts as a sensitive indicator of cellular metabolic states. With modern mass spectrometry technologies, particularly the high-throughput mass spectrometry platform provided by MtoZ Biolabs, researchers can accurately characterize dynamic HPr changes and elucidate their biological functions, providing powerful tools for studies of metabolic regulation, disease mechanisms, and precision medicine strategies.
MtoZ Biolabs, an integrated chromatography and mass spectrometry (MS) services provider.
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