Participation of DNA methylation in via Hedgehog transcriptional control in a murine model of LPS-induced neuroinflammation

Abstract

Neuroinflammation has been strongly associated as a risk factor for the development of neurodegenerative diseases. Although it is part of the natural aging process and acts in physiological defense processes, when in imbalance is related to the pathophysiology of neurodegenerative diseases. In contrast, the Hedgehog signaling pathway is known to play an important role in controlling neurogenesis and tissue repair in the central nervous system (CNS). Although there is little information on the impact of neuroinflammation on transcriptional control of the pathway, especially in the adult organism, evidence suggests that dysregulation of Ptchd1-Gli1 functions may lead to abnormal loss of glial precursor cells, progressive neural degeneration and installation of cognitive dysfunction and motor deficits. Among the mechanisms that act in the control of gene expression at the transcriptional level, we highlight the action of epigenetic mechanisms, mainly because they are highly sensitive to exogenous variations. Based on the information presented and knowing that the activation of the Hedgehog pathway is essential for maintaining neuronal activity in the adult brain, this proposal aims to characterize the transcriptional profile in different brain regions of the DNA methylation enzymes responsible for DNA methylation (DNMTs and TETs). ) and evaluate the methylation status of the gene promoter region [Sonic hedgehog (Shh); Patched (Ptch); Fusion Suppressor (Sufu) and Glioma 1-associated homologous Oncogene (Gli1)] 24 h after induction of neuroinflammation by intraperitoneal (i.p.) administration of lipopolysaccharide (LPS). The realization of this project will allow us, supported by the results obtained from the characterization of the transcriptional profile, to identify the brain regions most sensitive to epigenetic alterations, as well as to determine the effect of neuroinflammation on the methylation status of the promoter region of the Hedgehog pathway genes, which we will be able to study. Validate as a potential prognostic marker of the inflammatory phenotype in the Central Nervous System.