By Christina Towers, PhD.
In the last 20 years, epigenetic regulation has become front and center for almost all fields of biology and its role in diseases like cancer and neurodegeneration are being heavily studied. Epigenetics can be defined as a change in phenotype without a change in genotype that is caused by remodeling the chromatin landscape and is often mediated by changes in histone marks, like methylation, acetylation, phosphorylation, SUMOylation, ubiquitination, and glycosylation to name a few. The cellular recycling process of autophagy is among one of the many processes that is now known to be epigenetically regulated. Autophagy is induced during stress or nutrient deprivation and degrades damaged cytoplasmic material to generate building blocks to fuel metabolism. While initially thought to be an exclusively cytoplasmic process, recent studies have shown a nuclear component to autophagy regulation particularly through histone modifications, including methylation and acetylation.
Epigenetic activation of autophagy
Autophagy is a complex and tightly regulated process, most notably by the nutrient sensing mTOR pathway. Under basal conditions, mTORC complexes inhibit the upstream autophagy activating complexes. However, upon a dip in glucose availability or nutrients, activation of signaling cascades that inhibit the mTORC complexes subsequently induce autophagosome formation.
Epigenetic regulators include the methyltransferase, EZH2, which is recruited to gene promoters of several upstream mTORC inhibitors, including TSC2. EZH2 methylates and silences these autophagy activating promoters, and inhibition of EZH2 induces autophagy1.
A more direct activation of autophagy has been described, where the co-activator-associated arginine methyltransferase 1 (CARM1) increases the transcriptional activation of autophagy specific proteins. These effects are dependent on TFEB, a master regulator transcription factor of autophagy. This mechanism is regulated by nutrient availability as well; starvation induced activation of AMPK causes a transcriptional repression of SKP2, an E3 ubiquitin ligase that regulates the protein stability of CARM12.
Description: Step-by-step process of autophagy under the direct influence of epigenetics.
Epigenetic repression of Autophagy
In addition to activation, recent studies have also indicated an inhibitory role of epigenetics on autophagic turnover. Under basal conditions, the methyltransferase, G9a, interacts with autophagy proteins LC3B, WIPI1, and DOR gene promoters and represses gene expression. Starvation removes these silencing methylation marks on histones and activates autophagosome formation3. This work was recently extended upon to show that G9a and the bromo-domain containing protein BRD4 specifically target a novel TFEB/TFE3/MITF-independent transcriptional program in order to inhibit autophagy under basal conditions. Genetic and pharmacologic inhibition of BRD4 and/or G9a induces autophagy gene transcription and autophagic flux. However, after nutrient depletion, chromatin immunoprecipitation (ChIP) assays show an AMPK-dependent displacement of BRD4 on core autophagy gene promoters4.
Together, these studies highlight an important epigenetic component to autophagy regulation. Many, if not all, of these mechanisms are not autophagy specific and affect a host of other genes indicating the immediate need to further understand how epigenetic regulation may specifically affect autophagy. This is imperative, as many targeted therapeutics that affect epigenetic regulation, in addition to autophagy targeting agents, are moving through pre-clinical and clinical trials. These studies are beginning to hint that combinatory regiments may be more or less effective, depending on the context of the disease.
Explore Autophagy Signaling
Christina Towers, PhD
University of Colorado (AMC)
Dr. Towers studies the roles of autophagy, apoptosis and cell death in cancer.
- Wei, F. Z. et al. Epigenetic regulation of autophagy by the methyltransferase EZH2 through an MTOR-dependent pathway. Autophagy 11, 2309-2322, doi:10.1080/15548627.2015.1117734 (2015).
- Shin, H. J. et al. AMPK-SKP2-CARM1 signalling cascade in transcriptional regulation of autophagy. Nature 534, 553-557, doi:10.1038/nature18014 (2016).
- Artal-Martinez de Narvajas, A. et al. Epigenetic regulation of autophagy by the methyltransferase G9a. Mol Cell Biol 33, 3983-3993, doi:10.1128/MCB.00813-13 (2013).
- Sakamaki, J. I. et al. Bromodomain Protein BRD4 Is a Transcriptional Repressor of Autophagy and Lysosomal Function. Mol Cell 66, 517-532 e519, doi:10.1016/j.molcel.2017.04.027 (2017).