Studies on the epigenetic and transcriptional regulation of autophagy

Abstract

Autophagy is a highly conserved self-digestion process, essential to maintain homeostasis and viability in response to nutrient starvation. Although the components of autophagy in the cytoplasm have been well-studied, molecular basis for the epigenetic and transcriptional regulation of autophagy occurring in the nucleus is poorly understood. Here, I identify coactivator-associated arginine methyltransferase 1 (CARM1) as a novel component and followed histone H3R17 dimethylation as a critical epigenetic mark of autophagy. Intriguingly, CARM1 stability is regulated by SKP2-SCF (Skp1-Cullin1-F box protein) E3 ubiquitin ligase complex in the nucleus, but not in the cytoplasm, under nutrient-rich condition. Further, I found that nutrient starvation induced-AMP-activated protein kinase (AMPK) phosphorylates FOXO3a in the nucleus, which in turn transcriptionally represses SKP2 leading to increased CARM1 protein levels and subsequent increase in histone H3R17 dimethylation. CARM1 dynamically regulates the outcome of autophagy from the nucleus as genome-wide analyses reveal that CARM1 exerts transcriptional coactivator function on autophagy-related genes and lysosomal genes through Transcription Factor EB (TFEB). Taken together, my work unravels a new signaling axis of AMPK-SKP2-CARM1 in autophagy induction under nutrient starvation. My findings provide a conceptual advance that activation of specific epigenetic programs is indispensable for a sustained response to autophagy and demonstrate a previously unrecognized role of CARM1-dependent histone arginine methylation in the process of autophagy.