NEMoCuRe · Role of S-Nitrosylation of epigenetic modifiers in vascular regeneration

Role of S-Nitrosylation of epigenetic modifiers in vascular regeneration

What is the problem/issue being addressed? Humans have a limited capacity to regenerate and restore tissues and organs compared to lower vertebrates, such as zebrafish (Danio rerio). Understanding molecular mechanisms underpinning regenerative processes would pave the way for new therapies in humans. S-nitrosylation, the covalent attachment of a nitric oxide (NO) group to the thiol side chain of the cysteine, has emerged as an important mechanism for dynamic, posttranslational regulation of most or all main classes of protein. In addition, hypo- or hyper-S-nitrosylation of specific protein targets have been shown to be directly implicated in the etiology and symptomatology of an increasing number of cardiovascular disease. As for other posttranslational modifications, S-nitrosylation affects proteins in all cellular compartments. However, less is known about S-nitrosylation of chromatin modifiers. These are enzymes that modify the epigenome directly through DNA methylation or modifications of histones. S-nitrosylation could alter the activity of these chromatin modifiers and could promote an open chromatin state that is required for gene transcription during tissue repair. S-nitrosylation also plays a major role in the innate immune response to stress or injury, and pathogens. Therefore, modulating the immune system and its downstream pathways including iNOS, that catalyzes the NO production, could cause changes in S-nitrosylation, in particular of epigenetic modifiers, and eventually might be therapeutic in human disorders. The principle aim of this proposal is to explore mechanisms involving protein S-nitrosylation and their impact on tissue repair, specifically in vascular repair and regeneration. In particular, the adult zebrafish caudal fin completely regrows within a month upon amputation. Furthermore the vascular regeneration in this model can be easily followed under fluorescent microscopy using the transgenic line Tg(fli1:EGFP), where green fluorescent protein is expressed under control of an endothelial marker. Therefore, it will be adopted as a model of tissue injury/regeneration. Why is it important for society? The role of S-nitrosylation in the regulation of nuclear proteins, in particular of epigenetic modifiers, is almost completely unknown. This innovative project aims to establish whether S-nitrosylation of chromatin modifiers can create open epigenetic states that in turn favor cellular plasticity and promotes tissue regeneration. Insights from this proposal may lead to novel therapeutic approaches targeting cardiovascular disease by promoting vascular regeneration via mechanisms modulating the nitrosylation of key chromatin modifiers. What are the overall objectives? 1) Are there any changes in S-nitrosylation of epigenetic modifiers in zebrafish tailfin after injury? 2) Does S-nitrosylation of epigenetic modifiers affects vascular regeneration? 3) Is there any interaction between immune system, iNOS and S-nitrosylation of epigenetic modifiers?

Data: CORDIS, © European Union