Autophagy is an evolutionarily conserved catabolic process involved in several physiological and pathological processes1,2. Although primarily cytoprotective, autophagy can also contribute to cell death; it is thus important to understand what distinguishes the life or death decision in autophagic cells3. Here we report that induction of autophagy is coupled to reduction of histone H4 lysine 16 acetylation (H4K16ac) through downregulation of the histone acetyltransferase hMOF (also called KAT8 or MYST1), and demonstrate that this histone modification regulates the outcome of autophagy. At a genome-wide level, we find that H4K16 deacetylation is associated predominantly with the downregulation of autophagy-related genes. Antagonizing H4K16ac downregulation upon autophagy induction results in the promotion of cell death. Our findings establish that alteration in a specific histone post-translational modification during autophagy affects the transcriptional regulation of autophagy-related genes and initiates a regulatory feedback loop, which serves as a key determinant of survival versus death responses upon autophagy induction.
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We thank G. Mc Inerney, M. Malewicz, S. Orrenius and T. Panaretakis for discussion, and L. Guarente, V. Kaminskyy, M. Komatsu, G. Mc Inerney, M. Panas, R. G. Roeder and L. Xiaoling for reagents and cell lines. J.F. is supported by a fellowship from the Karolinska Institutet Foundations, M.A.L.-D. is partly supported by a Rackham Predoctoral Fellowship and W.L. is supported by breast cancer research Postdoctoral Fellowship Award (BC110381) from the US Department of Defense. This work was supported by a National Institutes of Health grant GM53396 (to D.J.K.) and National Institutes of Health/National Cancer Institute and Department of Defense grants (to M.G.R.), the Swedish Cancer Society, the Swedish Childhood Cancer Foundation (to B.J. and O.H.) and the Swedish Research Council (to B.J.). M.G.R. is an investigator of the Howard Hughes Medical Institute.
The authors declare no competing financial interests.
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Füllgrabe, J., Lynch-Day, M., Heldring, N. et al. The histone H4 lysine 16 acetyltransferase hMOF regulates the outcome of autophagy. Nature 500, 468–471 (2013). https://doi.org/10.1038/nature12313
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