Program in Translational Medicine, Department of Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo (EPM/UNIFESP), São Paulo, Brazil.
Division of Infectious Diseases, Escola Paulista de Medicina, Universidade Federal de São Paulo (EPM/UNIFESP), São Paulo, Brazil.
Shock. 2023 Jun 1;59(6):882-891. doi: 10.1097/SHK.0000000000002131. Epub 2023 Apr 19.
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.
脓毒症是全球发病率和死亡率的主要原因之一。单核细胞似乎在脓毒症过程中经历了功能重编程，导致宿主免疫反应失调。为了阐明这种失调机制，我们研究了参与固有免疫反应的基因启动子中发现的三种组蛋白修饰，并将这些发现与脓毒症患者的基因转录相关联。这些结果与目标基因的公共转录组数据和调节组蛋白修饰的表观遗传酶进行了比较。我们使用来自存活和非存活脓毒症患者以及健康志愿者的外周血单核细胞，通过 RT-qPCR 和 ChIP 分别评估参与固有免疫反应的基因的表达和其启动子中 H3K9ac、H3K4me3 和 H3K27me3 的富集。最后，我们使用转录组数据集来验证我们的发现。我们发现不同基因的染色质富集发生改变，抗炎细胞因子 IL-10 和抗菌基因 FPR1 的 H3K9ac 增加，与存活者相比，非存活者脓毒症患者的 IL-10 和 HLA-DR 启动子中的 H3K27me3 增加。这些改变与基因表达谱部分相关。此外，我们在转录组数据集中发现基因转录与调节这些组蛋白修饰的酶之间存在中等至强相关性。我们的研究是评估脓毒症患者样本的先驱研究之一，表明表观遗传酶调节参与免疫炎症反应的基因启动子中常见的组蛋白标记，在脓毒症期间改变这些特定基因的转录。此外，与存活者相比，非存活性脓毒症患者的表观遗传失调更为明显，表明其反应更为异常。
