ALTERED LEVELS OF H3K9AC, H3K4ME3, AND H3K27ME3 IN PROMOTERS OF DIFFERENTIALLY EXPRESSED GENES RELATED TO INNATE IMMUNE RESPONSE IN SEPTIC PATIENTS WITH DIFFERENT CLINICAL OUTCOMES.

ABSTRACT: Sepsis is one of the leading causes of morbidity and mortality worldwide. Monocytes seem to undergo functional reprogramming during sepsis, resulting in dysregulated host immune response. To clarify this dysregulation mechanism, we investigated three histone modifications found in promoters of genes involved in innate immune response, and associated these findings with gene transcription in septic patients. These results were compared with public transcriptome data of the target genes and epigenetic enzymes that modulate the histone modifications. We used peripheral blood mononuclear cell from surviving and nonsurviving septic patients, and healthy volunteers to evaluate the expression of genes involved in innate immune response and the enrichment of H3K9ac, H3K4me3, and H3K27me3 in their promoters, by RT-qPCR and ChIP, respectively. Finally, we used transcriptome data sets to validate our findings. We found alterations in the chromatin enrichment of different genes, with an increase in H3K9ac in the anti-inflammatory cytokine IL-10 and the antimicrobial gene FPR1 , as well as an increase in H3K27me3 in the IL-10 and HLA-DR promoter in nonsurvivors septic patients when compared with survivors. These alterations were partially associated with the gene expression profile. In addition, we found moderate to strong correlation between gene transcription and the enzymes that modulate these histone modifications in the transcriptome data sets. Our study, one of the pioneering by evaluating septic patients' samples, suggests that epigenetic enzymes modulate the prevalent histone marks in promoters of genes involved in the immune-inflammatory response, altering the transcription of these specific genes during sepsis. Furthermore, nonsurviving sepsis patients have a more pronounced epigenetic dysregulation compared with survivors, suggesting a more dysfunctional response.

Epigenetic Regulation in Sepsis, Role in Pathophysiology and Therapeutic Perspective.

Sepsis is characterized by an initial hyperinflammatory response, with intense cell activation and cytokine storm. In parallel, a prolonged compensatory anti-inflammatory response, known as immunological tolerance, can lead to immunosuppression. Clinically, this condition is associated with multiple organ failure, resulting in the patient's death. The mechanisms underlying the pathophysiology of sepsis are not yet fully understood, but evidence is strong showing that epigenetic changes, including DNA methylation and post-translational modifications of histones, modulate the inflammatory response of sepsis. During the onset of infection, host cells undergo epigenetic changes that favor pathogen survival. Besides, epigenetic changes in essential genes also orchestrate the patient's inflammatory response. In this review, we gathered studies on sepsis and epigenetics to show the central role of epigenetic mechanisms in various aspects of the pathogenesis of sepsis and the potential of epigenetic interventions for its treatment.