The Return of the Nucleus - Epigenetic Regulation of Autophagy

Autophagy is an evolutionary conserved catabolic process activated in response to a variety of cellular stresses, for example nutrient deprivation or chemotherapy. During autophagy, cells engulf parts of their cytplasm in a double-membrane vesicle, where misfolded proteins or damaged organelles are degraded. A plethora of human diseases has been linked to autophagy, including cancer and neurodegenerative disorders. Previously, autophagy has been considered a purely cytosolic event as even enucleated cells were able to display autophagic vesicles. Here we have shown for the first time that epigenetic changes are a major component of the autophagic process and involve global changes in the level of several histone modifications and local alterations in DNA methylation. Autophagy-related epigenetic modifications are involved during all stages of autophagy and have the potential to influence the autophagic life and death decision. During the early steps of autophagy, histone modifications are involved in the transcriptional up-regulation of autophagy-related genes. However, global down-regulation of histone H4 lysine 16 acetylation (H4K16ac) occurring at later stages protects cells from an overstimulation of autophagy, which can lead to a lethal level of autophagy. Furthermore, we have uncovered a critical role for the histone H3 lysine 36 (H3K36) demethylase Rph1/KDM4A in suppressing autophagy under baseline conditions. As we and others have shown that histone modifications are part of the autophagic process, we wondered how long the autophagy induced epigenetic modifications remain. By definition, an epigenetic regulation of autophagy should involve heritable changes that alter the cellular gene expression for a prolonged period of time. We indeed found that cancer cells in which autophagy has been induced show a lower expression of autophagy-related proteins. Upon renewed stimulation these pre-treated cells show an alteration in autophagic flux compared to untreated cells. This ‘autophagic memory’ involves an early up-regulation of DNA methyl transferase 3A (DNMT3A) which induces a stable down-regulation of autophagy-related genes by DNA methylation. In the future, development of new drugs for a variety of diseases involving deregulated autophagy may benefit from a widened knowledge about the epigenetic autophagy-regulatory network. LIST OF SCIENTIFIC PAPERS I. Opposing effects of hMOF and SIRT1 on H4K16 acetylation and the sensitivity to the topoisomerase II inhibitor etoposide. Hajji N, Wallenborg K, Vlachos P, Füllgrabe J, Hermanson O, Joseph B. Oncogene, 2010, 29(15):2192-204. II. The histone H4 lysine 16 acetyltransferase hMOF regulates the outcome of autophagy. Füllgrabe J, Lynch-Day MA, Heldring N, Li W, Struijk RB, Ma Q, Hermanson O, Rosenfeld MG, Klionsky DJ, Joseph B. Nature, 2013, 500(7463):468-71. III. Rph1/KDM4 mediates nutrient-limitation signaling that leads to the transcriptional induction of autophagy. Bernard A, Jin M, González-Rodríguez P, Füllgrabe J, Delorme-Axford E, Backues SK, Joseph B & Klionsky DJ. Current Biology, 2015, 25(5):546-55. IV. The DNA methyltransferase DNMT3A contributes to autophagy long-term memory. Füllgrabe J, González-Rodríguez P, Cheray M, Salli M, Heldring N, Dyczynski M, Li W, Rosenfeld MG and Joseph B. Manuscript. RELATED PUBLICATIONS, NOT INCLUDED IN THE THESIS I. Cracking the death code: apoptosis-related histone modifications. Füllgrabe J, Hajji N, Joseph B. Cell Death and Differentiation. 2010,17(8):1238-43. II. Histone onco-modifications. Füllgrabe J, Kavanagh E, Joseph B. Oncogene. 2011, 30(31):3391-403. III. Histone post-translational modifications regulate autophagy flux and outcome. Füllgrabe J, Klionsky DJ, Joseph B. Autophagy. 2013, 9(10):1621-3. IV. The return of the nucleus: transcriptional and epigenetic control of autophagy.. Füllgrabe J, Klionsky DJ, Joseph B. Nature Reviews Molecular Cell Biology. 2014, 15(1):65-74. V. Cracking the survival code: autophagy-related histone modifications. Füllgrabe J, Heldring N, Hermanson O, Joseph B. Autophagy. 2014, 10(4):556-61.