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Assays for Validating Histone Acetyltransferase Inhibitors
Published on: August 6, 2020
Ailanthone alleviates septic cardiomyopathy by attenuating MYST histone acetyltransferase 1 (MOF)-mediated H4K16
Yu Zhou1, Meican Ma2, Chong Xu3
1Clinical Research Center, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, China.
Insights
Lactate exacerbates septic cardiomyopathy by increasing histone lactylation (H4K16la), which activates inflammatory genes. Targeting this pathway with inhibitors like ailanthone may treat cardiac dysfunction in sepsis.
Area of Science:
- Biochemistry
- Epigenetics
- Cardiovascular Biology
Background:
- Elevated lactate is a biomarker for septic cardiomyopathy (SCM).
- Mechanisms linking lactate to SCM pathology are unclear.
- Histone lactylation is a potential epigenetic link.
Purpose of the Study:
- Investigate histone lactylation in sepsis-induced myocardial dysfunction.
- Identify epigenetic mechanisms of lactate's cardiac effects.
- Evaluate therapeutic potential of targeting lactate metabolism.
Main Methods:
- Assessed lactate effects on LPS-induced cardiomyocyte inflammation and apoptosis in vitro.
- Used CUT&Tag to study epigenetic mechanisms.
- Identified MOF as a lactyltransferase.
- Tested ailanthone (HK2 inhibitor) in a murine sepsis model.
Main Results:
- Lactate increased cardiomyocyte inflammation and apoptosis.
- Lactate upregulated histone H4 lysine 16 lactylation (H4K16la).
- H4K16la activated CXCL8 and CCL2 gene expression.
- MOF was identified as the lactyltransferase for H4K16la.
- Ailanthone treatment improved cardiac function in septic mice.
Conclusions:
- Lactate-driven H4K16la, via MOF, promotes inflammatory gene expression in SCM.
- The lactate-H4K16la pathway is a novel therapeutic target for SCM.
- HK2 inhibition shows therapeutic potential in sepsis-induced cardiac injury.
Background And Purpose:
Elevated circulating lactate is a recognized prognostic biomarker in septic cardiomyopathy (SCM), yet the mechanisms by which it exacerbates cardiac pathology are not fully understood. This study aims to investigate the role of histone lactylation as a novel epigenetic mechanism linking metabolic dysregulation to myocardial dysfunction in sepsis.
Experimental Approach:
The effects of lactate on lipopolysaccharide (LPS)-induced inflammation and apoptosis were assessed in cardiomyocytes in vitro. The underlying epigenetic mechanism was investigated using CUT&Tag. The role of MYST histone acetyltransferase 1 (MOF) as a lactyltransferase was determined through siRNA knockdown, co-immunoprecipitation and fluorescence co-localization assays. Furthermore, ailanthone (AIL), a specific hexokinase 2 (HK2) inhibitor identified through virtual screening, was evaluated for its therapeutic potential in a murine model of sepsis.
Key Results:
Lactate enhanced LPS-induced cardiomyocyte inflammation and apoptosis. Mechanistically, lactate upregulated histone H4 lysine 16 lactylation (H4K16la). This modification was enriched at the promoters of the CXCL8 and CCL2 genes to drive their transcriptional activation. We further identified MOF as a novel lactyltransferase directly catalysing H4K16la. In vivo, inhibition of HK2 with AIL attenuated myocardial injury and improved cardiac function in septic mice.
Conclusion And Implications:
Our findings reveal a pathogenic axis wherein lactate-driven H4K16la, mediated by MOF, promotes inflammatory gene expression in SCM. This identifies the lactate-H4K16la pathway as a potential therapeutic target for mitigating septic cardiomyopathy.
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