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Histone s-nitrosylation: new pathways in epigenetic regulation during sepsis

Grant number: 13/21026-8
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): June 01, 2014
Effective date (End): June 01, 2018
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Cooperation agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
Principal researcher:Francisco Garcia Soriano
Grantee:Ricardo Costa Petroni
Home Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:09/15530-0 - Sepsis - the role of inflammatory response: cell signaling; immune system action in sepsis; LPS tolerance and therapeutic, AP.TEM
Associated scholarship(s):15/15886-0 - Epigenetic factors that control acute leukemia cell differentiation, BE.EP.PD

Abstract

Despite advances in the understanding of sepsis pathogenesis, the mortality rate in patients with the disease remains high . Pathophysiological adaptations that regulate exacerbated inflammation act as important mechanisms of defense against endotoxemic shock. It is known that preconditioning with small doses of LPS (also known as LPS tolerance) decreases the inflammatory response triggered by the induction of sepsis. Currently, several studies have attributed the observed events in tolerance to low doses of LPS to epigenetic mechanisms, which would be responsible for the suppression of genes linked to pro-inflammatory response. Epigenetic modifications of histones H2A, H2B, H3 and H4, as methylation, acetylation and phosphorylation may direct affect the structural changes of the associated DNA through unknown mechanisms, thus modifying genes transcription. Nitric oxide (NO) is an important signaling molecule. NO play important physiological and pathophysiological roles in sepsis. Some studies have shown that besides the activation of inflammatory cells, NO is related to genes expression modulation. Our previous data show that the nitrosylation of histones is modulated in different ways by endotoxemia and tolerance to LPS. Several works show the influence of epigenetic regulation by methylation and histone acetylation. S-nitrosylation is a key mechanism in the regulation of several proteins and transcription factors. In this context, nitrosylation might play an important role in the regulation of histone gene transcription influencing the inflammatory process related to sepsis, which can be described as a new process for epigenetic regulation in this disease. The objective of this study is to investigate the role of S- nitrosylation of histone as a new mechanism of epigenetic regulation involved in sepsis. (AU)