Acetylation of histone 3 promotes miR-29a expression and downregulates STAT3 in sepsis

Area of Science:

• Molecular Biology
• Immunology
• Sepsis Pathophysiology

Background:

• MicroRNA-29a (miR-29a) targets Signal Transducer and Activator of Transcription 3 (STAT3), negatively regulating its expression.
• Both miR-29a and STAT3 are implicated in sepsis, with elevated miR-29a associated with the condition.
• The precise regulation of miR-29a during sepsis remains incompletely understood.

Purpose of the Study:

• To investigate the regulatory mechanisms of miR-29a expression in the context of sepsis.
• To elucidate the role of histone acetylation in miR-29a regulation.
• To determine the therapeutic potential of targeting miR-29a or STAT3 in sepsis.

Main Methods:

• TC-1 cells were treated with interleukin-6 (IL-6) to assess miR-29a and STAT3 expression.
• Cells were pre-treated with epigenetic modifiers (histone deacetylase and acetyltransferase inhibitors) before IL-6 stimulation.
• Expression of epigenetic enzymes, glycolysis, and apoptosis-related factors were measured.
• In vivo studies involved administering miR-29a or STAT3 inhibitors to septic mice to evaluate survival rates.

Main Results:

• IL-6 stimulation increased miR-29a expression while decreasing STAT3 levels.
• Histone acetylation was found to promote miR-29a expression.
• IL-6-induced glycolysis led to Acetyl-CoA accumulation, potentially influencing acetylation.
• In septic mice, miR-29a inhibition improved survival, whereas STAT3 inhibition worsened outcomes.
• The protective effect of miR-29a inhibition was abrogated by concurrent STAT3 inhibition.

Conclusions:

• Histone acetylation positively regulates miR-29a expression.
• Increased miR-29a, driven by histone acetylation, leads to STAT3 downregulation.
• This pathway contributes to sepsis exacerbation, highlighting a novel mechanism in sepsis pathophysiology.