Chromatin remodeling: demethylating H3K4me3 of type I IFNs gene by Rbp2 through interacting with Piasy for transcriptional attenuation

Abstract

Type I IFNs (IFNIs) are involved in the course of antiviral and antimicrobial activities; however, robust inductions of these can lead to host immunopathology. We have reported that the Pias (protein inhibitor of activated signal transducer and activator of transcription) family member, Piasy, possesses the ability to suppress IFNI transcriptions in mouse embryonic fibroblasts (MEFs), yet the specific molecular mechanism by which it acts remains elusive. Here, we identify that the H3K4me3 levels, one activation mark of genes, in MEFs that were stimulated by poly(I:C) were impaired by Piasy in the IFN-β gene. Piasy bound to the promoter region of the IFN-β gene in MEFs. Meanwhile, retinoblastoma binding protein 2 (Rbp2) was proven to be the only known and novel H3K4me3 demethylase that interacted with Piasy. Overexpression of Rbp2, but not its enzymatically inactive mutant Rbp2, retarded the transcription activities of IFNI, whereas small interfering RNA-mediated or short hairpin RNA-mediated knockdown of Rbp2 enhanced IFNI promoter responses. Above all, coexpression of Piasy and Rbp2 led to statistically less IFNI induction than overexpression of either Piasy or Rbp2 alone. Mechanistically, Piasy bound to the Jmjc domain (451-503 aa) of Rbp2 via its PINIT domain (101-218 aa), which is consistent with the domain required for their attenuation of transcription and H3K4me3 levels of IFNI genes. Our study demonstrates that Piasy may prevent exaggerated transcription of IFNI by Rbp2-mediated demethylation of H3K4me3 of IFNI, avoiding excessive immune responses.-Yu, X., Chen, H., Zuo, C., Jin, X., Yin, Y., Wang, H., Jin, M., Ozato, K., Xu, S. Chromatin remodeling: demethylating H3K4me3 of type I IFNs gene by Rbp2 through interacting with Piasy for transcriptional attenuation.

The Differences in the Proteome Profile of Cannabidiol-Treated Skin Fibroblasts following UVA or UVB Irradiation in 2D and 3D Cell Cultures

“…Cannabidiol (CBD) is a major, biologically active, phytocannabinoid that has recently become increasingly used in cytoprotection [1,2]. Since CBD does not show any psychoactive action, there are many efforts focused on the use of the anti-inflammatory and protective properties of CBD in different therapies [3,4]. To date, it has been shown that CBD can act as a reactive oxygen species (ROS) scavenger and as an antioxidant in cells under stress conditions [5].…”

Hypoxia stimulates SUMOylation-dependent stabilization of KDM5B

“…S5b). Similarly, KDM5B protein expression level was much lower in Pias4-/-MEF cells than in Pias4+/+ MEF cells 13 (Additional le: Fig. S5c).…”

“…Cell culture and small molecule chemical inhibitors Nine Human GC cell lines (SGC7901, BGC823, MKN45, AGS, HGC-27, MKN28, MGC803, N87, and MFC), a human normal gastric epithelial cell line (GES-1), and HEK293T were all purchased from Cell Bank of the Typical Culture Preservation Committee, Chinese Academy of Sciences (Shanghai, China). MEF cells from Pias4+/+ and Pias4-/mice were generous gifts from Prof. Shuai Ke (University of California, Los Angeles, Los Angeles, CA, USA) 13 . SGC7901/BGC823-shNC and SGC7901/BGC823-shKDM5B cells were generated via infection of lentiviral vectors containing shRNA (shscramble and shKDM5B) and puromycin selection.…”

Hypoxia Stimulates SUMOylation-Dependent Stabilization of KDM5B

“…As shown, KDM5B protein level was reduced in GC cells after PIAS4 knockdown (Figures 3A,B). Similarly, the KDM5B protein level was much lower in Pias4 −/− MEF cells than that of Pias4 +/+ MEF cells (Yu et al, 2018) (Supplementary Figure S4B). Meanwhile, the half-life of KDM5B protein was shortened in GC cells after PIAS4 knockdown under hypoxia conditions (Figures 3C,D).…”

“…Nine human GC cell lines (SGC7901, BGC823, MKN45, AGS, HGC-27, MKN28, MGC803, N87, and MFC), a normal human gastric epithelial cell line (GES-1), and HEK293T were all purchased from the Cell Bank of the Typical Culture Preservation Committee, Chinese Academy of Sciences (Shanghai, China). MEF cells from Pias4 +/+ and Pias4 −/− mice were generous gifts from Prof. Shuai Ke (University of California, Los Angeles, CA, United States) (Yu et al, 2018). SGC7901/ BGC823-shNC and SGC7901/BGC823-shKDM5B cells were generated via the infection of lentiviral vectors containing shRNA (shscramble and shKDM5B) and puromycin selection.…”