The histone H4 lysine 16 acetyltransferase hMOF regulates the outcome of autophagy

  • A Corrigendum to this article was published on 15 March 2017

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 (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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Figure 1: Autophagy is associated with reduced acetylation of histone H4 lysine 16.
Figure 2: Deacetylation of H4K16 by rapamycin treatment is associated with transcriptional regulation of autophagy-related genes.
Figure 3: Rapamycin-induced hMOF downregulation promotes deacetylation of H4K16.
Figure 4: Inhibition of H4K16ac downregulation upon autophagy induction results in cell death.

Change history

  • 21 August 2013

    An addition was made to the Acknowledgements section.

References

  1. 1

    Levine, B. & Kroemer, G. Autophagy in the pathogenesis of disease. Cell 132, 27–42 (2008)

    CAS  Article  Google Scholar 

  2. 2

    Mizushima, N., Levine, B., Cuervo, A. M. & Klionsky, D. J. Autophagy fights disease through cellular self-digestion. Nature 451, 1069–1075 (2008)

    ADS  CAS  Article  Google Scholar 

  3. 3

    Levine, B. & Yuan, J. Autophagy in cell death: an innocent convict? J. Clin. Invest. 115, 2679–2688 (2005)

    CAS  Article  Google Scholar 

  4. 4

    Yang, Z. & Klionsky, D. J. Eaten alive: a history of macroautophagy. Nature Cell Biol. 12, 814–822 (2010)

    CAS  Article  Google Scholar 

  5. 5

    Chen, Y. & Klionsky, D. J. The regulation of autophagy – unanswered questions. J. Cell Sci. 124, 161–170 (2011)

    CAS  Article  Google Scholar 

  6. 6

    Lee, I. H. & Finkel, T. Regulation of autophagy by the p300 acetyltransferase. J. Biol. Chem. 284, 6322–6328 (2009)

    CAS  Article  Google Scholar 

  7. 7

    Lee, I. H. et al. A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. Proc. Natl Acad. Sci. USA 105, 3374–3379 (2008)

    ADS  CAS  Article  Google Scholar 

  8. 8

    Yi, C. et al. Function and molecular mechanism of acetylation in autophagy regulation. Science 336, 474–477 (2012)

    ADS  CAS  Article  Google Scholar 

  9. 9

    Lin, S. Y. et al. GSK3–TIP60–ULK1 signaling pathway links growth factor deprivation to autophagy. Science 336, 477–481 (2012)

    ADS  CAS  Article  Google Scholar 

  10. 10

    Morselli, E. et al. Spermidine and resveratrol induce autophagy by distinct pathways converging on the acetylproteome. J. Cell Biol. 192, 615–629 (2011)

    CAS  Article  Google Scholar 

  11. 11

    Morselli, E. et al. Caloric restriction and resveratrol promote longevity through the Sirtuin-1-dependent induction of autophagy. Cell Death Dis. 1, e10 (2010)

    CAS  Article  Google Scholar 

  12. 12

    Vaquero, A., Sternglanz, R. & Reinberg, D. NAD+-dependent deacetylation of H4 lysine 16 by class III HDACs. Oncogene 26, 5505–5520 (2007)

    CAS  Article  Google Scholar 

  13. 13

    Hajji, N. et al. Opposing effects of hMOF and SIRT1 on H4K16 acetylation and the sensitivity to the topoisomerase II inhibitor etoposide. Oncogene 29, 2192–2204 (2010)

    CAS  Article  Google Scholar 

  14. 14

    Taipale, M. et al. hMOF histone acetyltransferase is required for histone H4 lysine 16 acetylation in mammalian cells. Mol. Cell. Biol. 25, 6798–6810 (2005)

    CAS  Article  Google Scholar 

  15. 15

    Smith, E. R. et al. A human protein complex homologous to the Drosophila MSL complex is responsible for the majority of histone H4 acetylation at lysine 16. Mol. Cell. Biol. 25, 9175–9188 (2005)

    CAS  Article  Google Scholar 

  16. 16

    Kouzarides, T. Chromatin modifications and their function. Cell 128, 693–705 (2007)

    CAS  Article  Google Scholar 

  17. 17

    Shogren-Knaak, M. et al. Histone H4–K16 acetylation controls chromatin structure and protein interactions. Science 311, 844–847 (2006)

    ADS  CAS  Article  Google Scholar 

  18. 18

    Kind, J. et al. Genome-wide analysis reveals MOF as a key regulator of dosage compensation and gene expression in Drosophila. Cell 133, 813–828 (2008)

    CAS  Article  Google Scholar 

  19. 19

    Core, L. J., Waterfall, J. J. & Lis, J. T. Nascent RNA sequencing reveals widespread pausing and divergent initiation at human promoters. Science 322, 1845–1848 (2008)

    ADS  CAS  Article  Google Scholar 

  20. 20

    Wang, D. et al. Reprogramming transcription by distinct classes of enhancers functionally defined by eRNA. Nature 474, 390–394 (2011)

    CAS  Article  Google Scholar 

  21. 21

    Ruthenburg, A. J. et al. Recognition of a mononucleosomal histone modification pattern by BPTF via multivalent interactions. Cell 145, 692–706 (2011)

    CAS  Article  Google Scholar 

  22. 22

    Wang, Z. et al. Genome-wide mapping of HATs and HDACs reveals distinct functions in active and inactive genes. Cell 138, 1019–1031 (2009)

    CAS  Article  Google Scholar 

  23. 23

    Katoh, H. et al. FOXP3 orchestrates H4K16 acetylation and H3K4 trimethylation for activation of multiple genes by recruiting MOF and causing displacement of PLU-1. Mol. Cell 44, 770–784 (2011)

    CAS  Article  Google Scholar 

  24. 24

    Zhou, Y. & Grummt, I. The PHD finger/bromodomain of NoRC interacts with acetylated histone H4K16 and is sufficient for rDNA silencing. Curr. Biol. 15, 1434–1438 (2005)

    CAS  Article  Google Scholar 

  25. 25

    Fullgrabe, J., Hajji, N. & Joseph, B. Cracking the death code: apoptosis-related histone modifications. Cell Death Differ. 17, 1238–1243 (2010)

    CAS  Article  Google Scholar 

  26. 26

    Kimura, S., Noda, T. & Yoshimori, T. Dissection of the autophagosome maturation process by a novel reporter protein, tandem fluorescent-tagged LC3. Autophagy 3, 452–460 (2007)

    CAS  Article  Google Scholar 

  27. 27

    Shechter, D., Dormann, H. L., Allis, C. D. & Hake, S. B. Extraction, purification and analysis of histones. Nature Protocols 2, 1445–1457 (2007)

    CAS  Article  Google Scholar 

  28. 28

    Burguillos, M. A. et al. Caspase signalling controls microglia activation and neurotoxicity. Nature 472, 319–324 (2011)

    ADS  CAS  Article  Google Scholar 

  29. 29

    Klionsky, D. J. et al. Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy 8, 445–544 (2012)

    CAS  Article  Google Scholar 

  30. 30

    Komatsu, M. et al. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J. Cell Biol. 169, 425–434 (2005)

    CAS  Article  Google Scholar 

  31. 31

    Cao, Y., Cheong, H., Song, H. & Klionsky, D. J. In vivo reconstitution of autophagy in Saccharomyces cerevisiae. J. Cell Biol. 182, 703–713 (2008)

    CAS  Article  Google Scholar 

  32. 32

    Shintani, T. & Klionsky, D. J. Cargo proteins facilitate the formation of transport vesicles in the cytoplasm to vacuole targeting pathway. J. Biol. Chem. 279, 29889–29894 (2004)

    CAS  Article  Google Scholar 

  33. 33

    Langmead, B., Trapnell, C., Pop, M. & Salzberg, S. L. Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 10, R25 (2009)

    Article  Google Scholar 

  34. 34

    Ji, H. et al. An integrated software system for analyzing ChIP-chip and ChIP-seq data. Nature Biotechnol. 26, 1293–1300 (2008)

    CAS  Article  Google Scholar 

  35. 35

    Saldanha, A. J. Java Treeview–extensible visualization of microarray data. Bioinformatics 20, 3246–3248 (2004)

    CAS  Article  Google Scholar 

  36. 36

    Ingolia, N. T., Ghaemmaghami, S., Newman, J. R. &, J. S. Genome-wide analysis in vivo of translation with nucleotide resolution using ribosome profiling. Science 324, 218–223 (2009)

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Acknowledgements

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.

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J.F., R.B.S. and B.J. performed experiments in mammalian cells. M.A.L.-D. performed yeast experiments. N.H. performed ChIP-seq. W.L. performed GRO-seq. N.H. and Q.M. performed bioinformatical analysis. J.F., O.H., M.G.R., D.J.K. and B.J. designed the study, and analysed and interpreted the data. The first draft of the paper was written by J.F. and B.J. All authors discussed the results and commented on or edited the manuscript. D.J.K. and B.J. share senior authorship of the paper.

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Correspondence to Bertrand Joseph.

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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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