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Manlio Vinciguerra — SIRT1 signaling and epigenetics during cellular stress

Speaker :

Manlio Vinciguerra, European Molecular Biology Laboratory (EMBL) Monterotondo (Rome)

When :

Wednesday 22 June at 11am

Where :

C023 (RDC LR6 côté Centre Blaise Pascal)

Title :

SIRT1 signaling and epigenetics during cellular stress

Abstract :

Metabolic syndrome and oxidative stress are risk factors for several kinds of diseases. SirT1 belongs to the sirtuin family of nicotinamide adenine dinucleotide NAD-dependent protein deacetylases, whose activation is considered beneficial for metabolic, cardiovascular and inflammatory diseases and to augment longevity. Its biological activity is believed to be at the crossroad between metabolic syndrome, oxidative stress and certain neoplastic processes. Using the murine heart as a model, we recently demonstrated that a locally acting isoform of insulin growth factor-1 (IGF-1) enhanced SirT1 expression in cardiomyocytes, exerting protection from hypertrophic and oxidative stresses and suggesting that these signaling pathways could represent a promising avenue for cardiac therapy. Combining Affymetrix microarray screening with ChIP-Seq for SirT1 in the heart of mice, we define a molecular network of new unexplored targets of mIGF-1/SirT1-dependent cardiac signaling, which await for functional validation. Given the high commercial interest in developing SirT1 activators to treat human metabolic, cardiovascular and neoplastic diseases, this integrated approach may accelerate the identification of druggable cardioprotective molecules. In fact, SirT1 deacetylates histones, cytoplasmic and nuclear proteins, regulating the compaction of chromatin and transcription. Chromatin compaction is regulated at several levels : one of these is the replacement of canonical histones with histone variants. MacroH2A1 is an histone variant of histone H2A, which modulates transcription and is involved in lipid metabolism. macroH2A1 is present in 2 isoforms, macroH2A1.1 and macroH2A1.2, generated upon alternative splicing. We found that macroH2A1.1 is strongly expressed in the heart and in post-mitotic tissues, whereas macroH2A1.2 is expressed in proliferating and cancer cells. Importantly, macroH2A1.1 binds with very tight affinity a unique metabolite produced by SirT1 enzymatic reaction, whereas macroH2A1.2 does not and that the two isoforms predict reliably cancer recurrence. We aim to understand in depth the various epigenetic roles of SirT1 during cellular metabolic&oxidative stress using a combination of mouse genetics, cell culture models, biochemical, high-throughput sequencing and imaging approaches.

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