title: The histone H4 lysine 16 acetyltransferase hMOF regulates the outcome of autophagy.
abstract: Autophagy is an evolutionarily conserved catabolic process involved in several physiological and pathological processes. 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 cells. 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.
authors.affiliation: Department of Oncology Pathology, Cancer Centrum Karolinska, Karolinska Institutet, Stockholm 17176, Sweden.
authors.forename: Jens
authors.initials: J
authors.lastname: Füllgrabe
authors.forename: Melinda A
authors.initials: MA
authors.lastname: Lynch-Day
authors.forename: Nina
authors.initials: N
authors.lastname: Heldring
authors.forename: Wenbo
authors.initials: W
authors.lastname: Li
authors.forename: Robert B
authors.initials: RB
authors.lastname: Struijk
authors.forename: Qi
authors.initials: Q
authors.lastname: Ma
authors.forename: Ola
authors.initials: O
authors.lastname: Hermanson
authors.forename: Michael G
authors.initials: MG
authors.lastname: Rosenfeld
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Klionsky
authors.forename: Bertrand
authors.initials: B
authors.lastname: Joseph
mesh_terms: D000107:Acetylation / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004843:Epistasis, Genetic / Q000187:drug effects; D025461:Feedback, Physiological; D051548:Histone Acetyltransferases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000737:chemistry / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics
chemical_list: D006657:Histones; D051548:Histone Acetyltransferases; C496552:KAT8 protein, human; D008239:Lysine; D020123:Sirolimus