The DNA methyltransferase DNMT3A contributes to autophagy long-term memory

Abstract

Macroautophagy/autophagy is a conserved catabolic pathway that targets cytoplasmic components for their degradation and recycling in an autophagosome-dependent lysosomal manner. Under physiological conditions, this process maintains cellular homeostasis. However, autophagy can be stimulated upon different forms of cellular stress, ranging from nutrient starvation to exposure to drugs. Thus, this pathway can be seen as a central component of the integrated and adaptive stress response. Here, we report that even brief induction of autophagy is coupled in vitro to a persistent downregulation of the expression of MAP1LC3 isoforms, which are key components of the autophagy core machinery. In fact, DNA-methylation mediated by de novo DNA methyltransferase DNMT3A of MAP1LC3 loci upon autophagy stimulation leads to the observed long-term decrease of MAP1LC3 isoforms at transcriptional level. Finally, we report that the downregulation of MAP1LC3 expression can be observed in vivo in zebrafish larvae and mice exposed to a transient autophagy stimulus. This epigenetic memory of autophagy provides some understanding of the long-term effect of autophagy induction and offers a possible mechanism for its decline upon aging, pathological conditions, or in response to treatment interventions.

Autophagy and Polyphenols in Osteoarthritis: A Focus on Epigenetic Regulation

“…Another study analyzes epigenetic memory of autophagy [ 77 ]. In this research they establish that there is a relationship between the stimulation of autophagy and the subsequent methylation of DNA by DNMT3A of MAP1LC3 which generates a prolonged decrease in the basal autophagy level through a persistent downregulation of MAP1LC3 [ 78 ].…”

Deep and fast label-free Dynamic Organellar Mapping

“…DNMT3B is a DNA methyl transferase. Interestingly, its close homologue DNMT3A has recently been shown to exert a ‘memory’ function in autophagy, by long-term regulation of expression of autophagy-associated genes upon starvation [43], suggesting a related function for DNMT3B. GK is a key modulator of energy and lipid metabolism; its association with the outer mitochondrial membrane is regulated by starvation [44], and this response is captured by our maps (Supplementary Table 2).…”

Inactivation of EGLN3 hydroxylase facilitates Erk3 degradation via autophagy and impedes lung cancer growth

“…2H and Supplementary Fig. 2E ), two well-known lysosome inhibitors [ 30 , 31 ]. Bafilomycin A1 restored Erk3 expression in KI macrophages (Fig.…”