Exogenous and endogenous HDAC inhibitor effects in Rubinstein-Taybi syndrome models
Di Fede, E.; Ottaviano, E.; Grazioli, P.; Ceccarani, C.; Parodi, C.; Colombo, E. A.; Bassanini, G.; Severgnini, M.; Milani, D.; Verduci, E.; Vaccari, T.; Massa, V.; Borghi, E.; Gervasini, C.
Show abstract
Rubinstein-Taybi syndrome (RSTS) is an autosomal dominant disorder with specific clinical signs and neurodevelopmental impairment. The two known proteins altered in the majority of RSTS patients are the histone acetylation regulators CBP and p300. For assessing possible ameliorative effects of exogenous and endogenous HDAC inhibitors (HDACi), we exploited in vivo and in vitro RSTS models. First, HDACi effects were tested on Drosophila melanogaster, showing molecular rescue. In the same model, we observed a shift in gut microbiota composition. We then studied HDACi effects in RSTS cell lines compared to healthy donor cells. We observed patients-specific molecular rescue of acetylation defects at subtoxic concentrations. Finally, we assessed commensal gut microbiota composition in a cohort of RSTS patients compared to healthy siblings. Intriguingly, we observed a significant depletion in butyrate-producing bacteria in RSTS patients. In conclusion, this study reports the possibility of modulating acetylation equilibrium by HDACi treatments and the importance of microbiota composition in a chromatinopathy.
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