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 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/KAT8/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 posttranslational 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.

Transcriptional and epigenetic profiling of nutrient-deprived cells to identify novel regulators of autophagy

“…In atg5 −/- mouse embryonic fibroblasts (MEFs), in contrast to WT MEFs, autophagy induction via rapamycin treatment does not lead to a decrease in H4K16ac, which is associated with downregulation of autophagy-associated genes and considered to be a feedback mechanisms [17]. This suggest that feedback at the transcriptional levels starts to become relevant after 6 h, or that these feedback loops are indirect, or that this is caused by differences between mice and men.…”

“…This discrepancy could be due to different methods to induce autophagy, for example nutrient deprivation versus MTOR inhibition, differences in timing, and differences in the type or species of the employed cells. For example, rapamycin-induced downregulation of H3K4me3 in MEFs is not observed after glucose starvation [16,17]. …”

“…EHMT2/G9a (euchromatic histone lysine methyltransferase 2) [14] and EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit) [15] have both been implicated in autophagy repression under serum starvation by increasing H3K9me2 and H3K27me3 histone mark levels, respectively, of certain autophagy-associated genes. Furthermore, autophagy induction has been demonstrated to affect total H3R17me2, H4K16ac, and H2BK120ub levels through CARM1 (coactivator associated arginine methyltransferase 1) [16], KAT8/hMOF (lysine acetyltransferase 8) [17], and the deubiquitinase USP44 (ubiquitin specific peptidase 44) [18], respectively. These alterations affect transcription of genes involved in (the regulation of) autophagy and therefore function as an epigenetic switch in autophagy regulation under various starvation conditions and upon MTOR (mechanistic target of rapamycin kinase) inhibition.…”

“…For example, autophagy induction downregulates KAT8, thereby decreasing H4K16 acetylation of autophagy-associated genes, which results in decreased gene expression. This reduces autophagy, thereby providing a feedback mechanism to control the amount of autophagy [17]. Furthermore, global changes in H4K20me3 [19], H3K4me3 [17], and H3K56ac [20] have been associated with autophagy induction, but whether and how this affects autophagy remains to be determined [17,19,20].…”

“…This reduces autophagy, thereby providing a feedback mechanism to control the amount of autophagy [17]. Furthermore, global changes in H4K20me3 [19], H3K4me3 [17], and H3K56ac [20] have been associated with autophagy induction, but whether and how this affects autophagy remains to be determined [17,19,20]. Importantly, extensive studies which assess and combine genome-wide transcriptomic and epigenomic events underlying autophagy are lacking.…”