Epigenetic Regulation in Sepsis, Role in Pathophysiology and Therapeutic Perspective

Falcão-Holanda, Renata Brito; Brunialti, Milena Karina Coló; Jasiulionis, Miriam Galvonas; Salomão, Reinaldo

doi:10.3389/fmed.2021.685333

Cited by 18 publications

(19 citation statements)

References 94 publications

(126 reference statements)

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“…We anticipate that single-cell RNA sequencing, as has been previously demonstrated [58], may further delineate cell-speci c molecular targets correlated with development of organ dysfunctions. 7) Finally, transcription is tightly regulated by epigenomic changes, which are known to themselves modulate development of organ dysfunctions [59]. Future studies that integrate transcriptomic and epigenomic shifts in sepsis may enable discovery of novel epigenetic therapies that correspond with patient endotypes.…”

Section: Discussionmentioning

confidence: 99%

Machine learning driven identification of gene-expression signatures correlated with multiple organ dysfunction trajectories and complex sub-endotypes of pediatric septic shock

Atreya

Banerjee

Lautz

et al. 2022

Preprint

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Background Multiple organ dysfunction syndrome (MODS) disproportionately drives sepsis morbidity and mortality among children. The biology of this heterogeneous syndrome is complex, dynamic, and incompletely understood. Gene expression signatures correlated with MODS trajectories may facilitate identification of molecular targets and predictive enrichment. Methods Secondary analyses of publicly available datasets. (1) Supervised machine learning (ML) was used to identify genes correlated with persistent MODS relative to those without in the derivation cohort. Model performances were tested across 4 validation cohorts, among children and adults with differing inciting cause for organ dysfunctions, to identify a stable set of genes and fixed classification model to reliably estimate the risk of MODS. Clinical propensity scores, where available, were used to enhance model performance. (2) We identified organ-specific dysfunction signatures by eliminating redundancies between the shared MODS signature and those of individual organ dysfunctions. (3) Finally, novel patient subclasses were identified through unsupervised hierarchical clustering of genes correlated with persistent MODS and compared with previously established pediatric septic shock endotypes. Results 568 genes were differentially expressed, among which ML identified 109 genes that were consistently correlated with persistent MODS. The AUROC of a model that incorporated the stable features chosen from repeated cross-validation experiments to estimate risk of MODS was 0.87 (95% CI: 0.85–0.88). Model performance using the top 20 genes and an ExtraTree classification model yielded AUROCs ranging 0.77–0.96 among validation cohorts. Genes correlated with day 3 and 7 cardiovascular, respiratory, and renal dysfunctions were identified. Finally, the top 50 genes were used to discover four novel subclasses, of which patients belonging to M1 and M2 had the worst clinical outcomes. Reactome pathway analyses revealed a potential role of transcription factor RUNX1 in distinguishing subclasses. Interaction with receipt of adjuvant steroids suggested that newly derived M1 and M2 endotypes were biologically distinct relative to established endotypes. Conclusions Our data suggest the existence of complex sub-endotypes among children with septic shock wherein overlapping biological pathways may be linked to differential response to therapies. Future studies in cohorts enriched for patients with MODS may facilitate discovery and development of disease modifying therapies for subsets of critically ill children with sepsis.

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Section: Discussionmentioning

confidence: 99%

Machine learning driven identification of gene-expression signatures correlated with multiple organ dysfunction trajectories and complex sub-endotypes of pediatric septic shock

Atreya

Banerjee

Lautz

et al. 2022

Preprint

View full text Add to dashboard Cite

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“…Non-coding (ncRNAs) play an important role in the pathogenesis of sepsis [ 177 ]. Analysis of the co-expression network of protein-coding and long ncRNAs (lncRNAs) in septic and healthy neutrophils indicates that some of the lncRNAs alter gene expression, regulate the translation of proteins, and are involved in regulatory loops during sepsis [ 178 ].…”

Section: Sirtuins and Epigenetic Regulation Of Sepsismentioning

confidence: 99%

Sirtuins and Sepsis: Cross Talk between Redox and Epigenetic Pathways

2021

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Sepsis and septic shock are the leading causes of death among hospitalized patients in the US. The immune response in sepsis transitions from a pro-inflammatory and pro-oxidant hyper-inflammation to an anti-inflammatory and cytoprotective hypo-inflammatory phase. While 1/3rd sepsis-related deaths occur during hyper-, a vast majority of sepsis-mortality occurs during the hypo-inflammation. Hyper-inflammation is cytotoxic for the immune cells and cannot be sustained. As a compensatory mechanism, the immune cells transition from cytotoxic hyper-inflammation to a cytoprotective hypo-inflammation with anti-inflammatory/immunosuppressive phase. However, the hypo-inflammation is associated with an inability to clear invading pathogens, leaving the host susceptible to secondary infections. Thus, the maladaptive immune response leads to a marked departure from homeostasis during sepsis-phases. The transition from hyper- to hypo-inflammation occurs via epigenetic programming. Sirtuins, a highly conserved family of histone deacetylators and guardians of homeostasis, are integral to the epigenetic programming in sepsis. Through their anti-inflammatory and anti-oxidant properties, the sirtuins modulate the immune response in sepsis. We review the role of sirtuins in orchestrating the interplay between the oxidative stress and epigenetic programming during sepsis.

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“…Epigenetic alterations, especially changes in DNA methylation, have been found to be associated with a variety of diseases, including sepsis (7)(8)(9). Several studies have revealed differential methylation profiles which were correlated with sepsis status both in adults and neonates (10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

Role of Age-Related Changes in DNA Methylation in the Disproportionate Susceptibility and Worse Outcomes of Sepsis in Older Adults

et al. 2022

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Sepsis, a complex multisystem disorder, is among the top causes of hospitalization and mortality in older adults. However, the mechanisms underlying the disproportionate susceptibility to sepsis and worse outcomes in the elderly are not well understood. Recently, changes in DNA methylation have been shown to be linked to aging processes and age-related diseases. Thus, we postulated that age-related changes in DNA methylation may play a role in the onset and prognosis of sepsis in elderly patients. Here, we performed genome-wide methylation profiling of peripheral blood from patients with sepsis and controls. Among the CpG sites whose methylation changes may contribute to an increase in sepsis susceptibility or mortality, 241 sites that possessed age-related changes in DNA methylation in controls may partly explain the increased risk of sepsis in older adults, and 161 sites whose methylation significantly correlated with age in sepsis group may be the potential mechanisms underlying the worse outcomes of elderly septic patients. Finally, an independent cohort was used to validate our findings. Together, our study demonstrates that age-related changes in DNA methylation may explain in part the disproportionate susceptibility and worse outcomes of sepsis in older adults.

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Epigenetic Regulation in Sepsis, Role in Pathophysiology and Therapeutic Perspective

Cited by 18 publications

References 94 publications

Machine learning driven identification of gene-expression signatures correlated with multiple organ dysfunction trajectories and complex sub-endotypes of pediatric septic shock

Machine learning driven identification of gene-expression signatures correlated with multiple organ dysfunction trajectories and complex sub-endotypes of pediatric septic shock

Sirtuins and Sepsis: Cross Talk between Redox and Epigenetic Pathways

Role of Age-Related Changes in DNA Methylation in the Disproportionate Susceptibility and Worse Outcomes of Sepsis in Older Adults

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