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Carrasqueiro, Gabriela

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  • Epigenetic alterations in sepsis
    Publication . Carrasqueiro, Gabriela Teixeira; Castelo-Branco, Pedro; Binnie, Alexandra
    Sepsis is a life-threatening complication of infection. Typically, a localized infection triggers a systemic inflammatory cascade resulting in widespread organ damage, organ failure, and often death. Of the 31.5 million cases of sepsis worldwide annually, it is estimated that there are 5.3 million deaths (Fleischmann et al., 2016). The pathophysiology of sepsis involves widespread reprogramming of gene expression. Bioinformatic approaches have revealed multiple gene pathways that are activated or inhibited in sepsis (DC Angus and Tom Van der Poll et al., 2013). Epigenetic mechanisms, including histone modifications, DNA methylation, and non-coding RNAs (such as microRNAs, siRNAs, andribosomal RNAs) are master regulators of gene expression in both normal and pathological states. Although there is limited data on epigenetic regulation of sepsis, localized epigenetic changes have been identified in individual genes.However no genome-wide data has yet been published. In this studywe define a number of sepsis-related DNA methylation changes in sepsis-associated genes. We correlate these changes with gene expression and with clinically-relevant outcomes. Finally, we will investigate the mechanisms by which DNA methylation regulates individual gene expression in sepsis.
  • Epigenetic profiling in severe sepsis: a pilot study of DNA methylation profiles in critical illness
    Publication . Binnie, Alexandra; Walsh, Christopher J.; Hu, Pingzhao; Dwivedi, Dhruva J.; Fox-Robichaud, Alison; Liaw, Patricia C.; Tsang, Jennifer L. Y.; Batt, Jane; Carrasqueiro, Gabriela; Gupta, Sahil; Marshall, John C.; Castelo-Branco, Pedro; dos Santos, Claudia C.
    Objectives: Epigenetic alterations are an important regulator of gene expression in health and disease; however, epigenetic data in sepsis are lacking. To demonstrate proof of concept and estimate effect size, we performed the first epigenome-wide methylation analysis of whole blood DNA samples from a cohort of septic and nonseptic critically ill patients. Design: A nested case-control study using genomic DNA isolated from whole blood from septic (n = 66) and nonseptic (n = 68) critically ill patients on "Day 1" of ICU admission. Methylation patterns were identified using Illumina 450K arrays with percent methylation expressed as beta values. After quality control, 134 participants and 414,818 autosomal cytosine-phosphate-guanine sites were used for epigenome-wide methylation analyses. Setting: Tertiary care hospitals. Subjects: Critically ill septic and nonseptic patients. Interventions: Observational study. Measurements and Main Results: A total of 668 differentially methylated regions corresponding to 443 genes were identified. Known sepsis-associated genes included complement component 3; angiopoietin 2; myeloperoxidase; lactoperoxidase; major histocompatibility complex, class I, A; major histocompatibility complex, class II, isotype DR beta I; major histocompatibility complex, class I, C; and major histocompatibility complex, class II, isotype DQ beta I. When compared with whole blood gene expression data from seven external datasets containing septic and nonseptic patients, 81% of the differentially methylated region-associated genes were differentially expressed in one or more datasets and 31% in three or more datasets. Functional analysis showed enrichment for antigen processing and presentation, methyltransferase activity, cell adhesion, and cell junctions. Analysis by weighted gene coexpression network analysis revealed DNA comethylation modules that were associated with clinical traits including severity of illness, need for vasopressors, and length of stay. Conclusions: DNA methylation marks may provide important causal and potentially biomarker information in critically ill patients with sepsis.
  • Epigenetics of sepsis
    Publication . Binnie, Alexandra; Tsang, Jennifer L. Y.; Hu, Pingzhao; Carrasqueiro, Gabriela; Castelo-Branco, Pedro; dos Santos, Claudia C.
    Recent evidence from the fields of microbiology and immunology, as well as a small number of human sepsis studies, suggest that epigenetic regulation may play a central role in the pathogenesis of sepsis. The term "epigenetics" refers to regulatory mechanisms that control gene expression but are not related to changes in DNA sequence. These include DNA methylation, histone modifications, and regulation of transcription via non-coding RNAs. Epigenetic modifications, occurring in response to external stressors, lead to changes in gene expression, and thus lie at the intersection between genetics and the environment. In this review, we examine data from in vitro studies, animal studies, and the existing human sepsis studies in epigenetics to demonstrate that epigenetic mechanisms are likely central to the pathogenesis of sepsis and that epigenetic therapies may have potential in the treatment of sepsis and its associated organ failures.