Transcriptional regulation of autophagy by chromatin remodeling complex and histone variant

Abstract

ABSTRACT Autophagy is a catabolic process to maintain homeostasis, and involved in cell differentiation and development. Autophagy is tightly regulated in response to nutrient availability but the underlying mechanism is not completely understood. Recently, we identified the chromatin remodeling complex INO80 (inositol-requiring mutant 80) and histone variant H2A.Z as new autophagy regulators and uncover how histone deacetylase Rpd3L (reduced potassium dependency 3 large) complex represses autophagy by deacetylating Ino80 and H2A.Z. In particular, Rpd3L complex deacetylates Ino80 at lysine 929, which protects Ino80 from being degraded by autophagy. The stabilized Ino80 then evicts H2A.Z from autophagy-related (ATG) genes, leading to their transcriptional repression. In parallel, Rpd3L complex also deacetylates H2A.Z, which further reduces its association with ATG gene promoters and repress ATG gene transcription. Under nutrient-rich conditions, Rpd3L-mediated deacetylation of Ino80 K929 and H2A.Z is enhanced by the TORC1 complex (target of rapamycin complex 1). Under nitrogen-starvation condition, TORC1 is inactivated, leading to reduced activity of Rpd3L complex and increased acetylation of Ino80 and H2A.Z, which in turn induce the transcription of ATG genes. These results reveal a critical role of chromatin remodelers and histone variants in regulating autophagy in response to nutrient availability. Abbreviations: INO80: inositol-requiring mutant 80; Rpd3: reduced potassium dependency 3; H2A.Z: histone H2A variant; Rpd3L complex: Rpd3 large complex; H4K16: H4 lysine 16; H3R17: H3 arginine 17; H3T11: H3 threonine 11; TORC1 complex: target of rapamycin complex 1; ATG: autophagy-related; SWI/SNF: switch/sucrose non-fermentable; SWR1: Swi2/Snf2-related ATPase complex; RSC: remodel the structure of chromatin; ISWI: imitation switch; CHD1: chromodomain helicase DNA binding protein 1; Arp8: actin-related protein 8; Sds3: suppressor of defective silencing 3; Ume6: unscheduled meiotic gene expression 6