SIRT6 promotes transcription of a subset of NRF2 targets by mono-ADP-ribosylating BAF170

• Published in: Nucleic acids research 2019-09, Vol.47 (15), p.7914-7928
• Main Authors: Rezazadeh, Sarallah, Yang, David, Tombline, Gregory, Simon, Matthew, Regan, Sean P, Seluanov, Andrei, Gorbunova, Vera
• Format: Article
• Language: English
• Subjects: ADP-Ribosylation; Animals; Cell Line; Chromatin - chemistry; Chromatin - drug effects; Chromatin - metabolism; Chromosomal Proteins, Non-Histone - genetics; Chromosomal Proteins, Non-Histone - metabolism; DNA-Binding Proteins; Embryo, Mammalian; Enhancer Elements, Genetic; Fibroblasts - cytology; Fibroblasts - drug effects; Fibroblasts - metabolism; Gene Expression Regulation; Gene regulation, Chromatin and Epigenetics; Heme Oxygenase-1 - genetics; Heme Oxygenase-1 - metabolism; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Knockout; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Oxidative Stress; Paraquat - pharmacology; Protein Binding; RNA Polymerase II - genetics; RNA Polymerase II - metabolism; Signal Transduction; Sirtuins - deficiency; Sirtuins - genetics; Transcription Factors; Transcription, Genetic
• ISSN: 0305-1048; 1362-4962
• DOI: 10.1093/nar/gkz528

Abstract SIRT6 is critical for activating transcription of Nuclear factor (erythroid-derived 2)-like 2 (NRF2) responsive genes during oxidative stress. However, while the mechanism of SIRT6-mediated silencing is well understood, the mechanism of SIRT6-mediated transcriptional activation is unknown. Here, we employed SIRT6 separation of function mutants to reveal that SIRT6 mono-ADP-ribosylation activity is required for transcriptional activation. We demonstrate that SIRT6 mono-ADP-ribosylation of BAF170, a subunit of BAF chromatin remodeling complex, is critical for activation of a subset of NRF2 responsive genes upon oxidative stress. We show that SIRT6 recruits BAF170 to enhancer region of the Heme oxygenase-1 locus and promotes recruitment of RNA polymerase II. Furthermore, SIRT6 mediates the formation of the active chromatin 10-kb loop at the HO-1 locus, which is absent in SIRT6 deficient tissue. These results provide a novel mechanism for SIRT6-mediated transcriptional activation, where SIRT6 mono-ADP-ribosylates and recruits chromatin remodeling proteins to mediate the formation of active chromatin loop.