title: Epigenetic and transcriptional regulation of autophagy.
abstract: Macroautophagy (hereafter referred to as autophagy) is an essential self-digestion process to maintain homeostasis and promote survival in response to starvation. Although the components of autophagy in the cytoplasm have been well studied, little has been known about the fine-tuning mechanism of autophagy through epigenetic regulations. Recently, we identified the histone arginine methyltransferase CARM1 as a new component and followed histone H3R17 dimethylation as a critical epigenetic mark in starvation-induced autophagy. Upon nutrient starvation, CARM1 is stabilized in the nucleus, but not in the cytoplasm, whereas it is constantly degraded under nutrient-rich conditions by the SKP2-containing SCF (SKP1-CUL1-F-box protein) E3 ubiquitin ligase. We further showed that nutrient starvation induces the protein levels and activity of AMPK in the nucleus. Activated AMPK then phosphorylates FOXO3, leading to SKP2 downregulation and increased CARM1 protein levels in the nucleus. Stabilized CARM1 in turn functions as an essential co-activator of TFEB and regulates the expression of autophagy and lysosomal genes. Our findings provide a conceptual advance that activation of specific epigenetic programs is indispensable for a sustained autophagic response, and shed light on a potential therapeutic targeting of the newly identified AMPK-SKP2-CARM1 signaling axis in autophagy-related diseases.
authors.affiliation: a Creative Research Initiatives Center for Chromatin Dynamics, School of Biological Sciences , Seoul National University , Seoul , South Korea.
authors.forename: Hi-Jai R
authors.initials: HR
authors.lastname: Shin
authors.affiliation: a Creative Research Initiatives Center for Chromatin Dynamics, School of Biological Sciences , Seoul National University , Seoul , South Korea.
authors.forename: Hyunkyung
authors.initials: H
authors.lastname: Kim
authors.affiliation: b Department of Biological Sciences , Sookmyung Women's University , Seoul , South Korea.
authors.forename: Keun Il
authors.initials: KI
authors.lastname: Kim
authors.affiliation: a Creative Research Initiatives Center for Chromatin Dynamics, School of Biological Sciences , Seoul National University , Seoul , South Korea.
authors.forename: Sung Hee
authors.initials: SH
authors.lastname: Baek
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics*; D044127:Epigenesis, Genetic; D006801:Humans; D051379:Mice; D008954:Models, Biological; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D011484:Protein-Arginine N-Methyltransferases; C119966:coactivator-associated arginine methyltransferase 1
keywords: AMPK; CARM1; FOXO; SKP2; TFEB; arginine methylation; ellagic acid; epigenetic regulation; starvation; transcription