Chiara Collesi1,2,3, Giulia Felician1, Ilaria Secco1, Maria Ines Gutierrez1, Elisa Martelletti1, Hashim Ali1, Lorena Zentilin1, Michael P Myers4, Mauro Giacca1,2,3. 1. Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB), Padriciano 99, 34149 Trieste, Italy. 2. Department of Medical, Surgical and Health Sciences, University of Trieste, Strada di Fiume 447, 34100 Trieste, Italy. 3. Center for Translational Cardiology, Azienda Sanitaria Universitaria Integrata, Via Valdoni 7, 34100 Trieste, Italy; and. 4. Protein Networks Laboratories, International Centre for Genetic Engineering and Biotechnology (ICGEB), Padriciano 99, 34149 Trieste, Italy.
Abstract
Aims: The Notch signalling pathway regulates the balance between proliferation and differentiation in several tissues, including the heart. Our previous work has demonstrated that the proliferative potential of neonatal cardiomyocytes relies on Notch1 activity. A deep investigation on the biochemical regulation of the Notch signalling in cardiomyocytes is the focus of the current research. Methods and results: We show that the Notch1 intracellular domain is acetylated in proliferating neonatal rat cardiomyocytes and that acetylation tightly controls the amplitude and duration of Notch signalling. We found that acetylation extends the half-life of the protein, and enhanced its transcriptional activity, therefore counteracting apoptosis and sustaining cardiomyocyte proliferation. Sirt1 acted as a negative modulator of Notch1 signalling; its overexpression in cardiomyocytes reverted Notch acetylation and dampened its stability. A constitutively acetylated fusion protein between Notch1 and the acetyltransferase domain of p300 promoted cardiomyocyte proliferation, which was remarkably sustained over time. Viral vector-mediated expression of this protein enhanced heart regeneration after apical resection in neonatal mice. Conclusion: These results identify the reversible acetylation of Notch1 as a novel mechanism to modulate its signalling in the heart and tune the proliferative potential of cardiomyocytes. Published on behalf of the European Society of Cardiology. All rights reserved.
Aims: The Notch signalling pathway regulates the balance between proliferation and differentiation in several tissues, including the heart. Our previous work has demonstrated that the proliferative potential of neonatal cardiomyocytes relies on Notch1 activity. A deep investigation on the biochemical regulation of the Notch signalling in cardiomyocytes is the focus of the current research. Methods and results: We show that the Notch1 intracellular domain is acetylated in proliferating neonatal rat cardiomyocytes and that acetylation tightly controls the amplitude and duration of Notch signalling. We found that acetylation extends the half-life of the protein, and enhanced its transcriptional activity, therefore counteracting apoptosis and sustaining cardiomyocyte proliferation. Sirt1 acted as a negative modulator of Notch1 signalling; its overexpression in cardiomyocytes reverted Notch acetylation and dampened its stability. A constitutively acetylated fusion protein between Notch1 and the acetyltransferase domain of p300 promoted cardiomyocyte proliferation, which was remarkably sustained over time. Viral vector-mediated expression of this protein enhanced heart regeneration after apical resection in neonatal mice. Conclusion: These results identify the reversible acetylation of Notch1 as a novel mechanism to modulate its signalling in the heart and tune the proliferative potential of cardiomyocytes. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Daniel Antfolk; Christian Antila; Kati Kemppainen; Sebastian K-J Landor; Cecilia Sahlgren Journal: Biochim Biophys Acta Mol Cell Res Date: 2019-07-11 Impact factor: 4.739
Authors: Marijn C Peters; Sofia Di Martino; Thomas Boelens; Jiabin Qin; Alain van Mil; Pieter A Doevendans; Steven A J Chamuleau; Joost P G Sluijter; Klaus Neef Journal: Mol Ther Methods Clin Dev Date: 2022-02-23 Impact factor: 6.698