Dataset Information

An NF-κB-responsive long noncoding RNA, PINT, regulates inflammatory gene transcription by scaffolding p65 and EZH2

ABSTRACT: Long non-coding RNAs (lncRNAs) are central regulators of the inflammatory response and play an important role in inflammatory diseases. PINT has been reported to be involved in tissue development and tumorigenesis. However, potential functions of PINT in the innate immune system are largely unknown. Here, we report a specific role for PINT in activating inflammatory gene transcription. The expression of PINT is primarily dependent on the NF-κB signaling pathway in macrophages and intestinal epithelial cells. Functionally, PINT selectively promotes the expression of inflammatory genes, including TNF-α, in basal and LPS-stimulated cells. Mechanistically, PINT acts as a modular scaffold of p65 and EZH2 to coordinate their localization and specify their binding to the target genes. Further, a high expression of PINT is detected in the intestinal tissue from patients with Inflammatory Bowel Disease (IBD). Together, these findings demonstrate that PINT acts as an activator of inflammatory responses, highlighting the importance of this lncRNA in inflammatory diseases as a potential therapeutic target.

ORGANISM(S): Homo sapiens

PROVIDER: GSE139278 | GEO | 2022/10/01

REPOSITORIES: GEO

ACCESS DATA

Similar Datasets

Project description:Background: Atherosclerosis leads high mortality, highlighting an urgent need for new therapeutic strategies. Protein kinases orchestrate multiple cellular events in atherosclerosis and may provide new therapeutic targets for atherosclerosis. Here, we identified a protein kinase, WEE1 G2 checkpoint kinase (WEE1), promoting inflammatory response in atherosclerosis. Methods: The ApoE-/- mice without macrophage-specific WEE1 deletion (ApoE-/-WEE1f/f) and ApoE-/- mice with macrophage-specific WEE1 deletion (ApoE-/-WEE1MCKO) were generated using bone marrow transplantation. These mice and WEE1 inhibitor MK1775 were used in a high-fat diet (HFD)-induced atherosclerotic model. Human atherosclerotic tissues, mouse primary peritoneal macrophages (MPMs), 293T cells, and recombinant proteins were utilized to investigate the pathogenic role and underlying mechanisms of WEE1. Results: We identified up-regulated p-WEE1 in macrophages in atherosclerotic lesions of HFD-fed ApoE-/- mice. Transcriptome sequencing analysis indicated that WEE1 promotes oxLDL-induced inflammation in macrophages. We then demonstrated that macrophage-specific deletion or pharmacological inhibition of WEE1 attenuates atherosclerosis by reducing inflammation both in vivo and in vitro. The overexpression of wild-type WEE1 or activating-mutant WEE1, but not inactivating-mutant WEE1, exacerbates inflammation in macrophages. Mechanistically, transcriptome sequencing analysis and co-immunoprecipitation followed by quantitative proteomics analysis identified p65 as a binding protein of WEE1. We confirmed that WEE1 directly interacts with the RHD domain of p65 via kinase domain and phosphorylates p65 at S536, thereby facilitating subsequent NF-κB activation and inflammatory response in macrophages. Conclusions: Our findings demonstrated that macrophage WEE1 promotes inflammatory atherosclerosis by directly binding to p65 and phosphorylate it at S536. This study provides WEE1 as a new p65 regulator in inflammation and a potential therapeutic target for atherosclerosis.

Dataset Information

An NF-κB-responsive long noncoding RNA, PINT, regulates inflammatory gene transcription by scaffolding p65 and EZH2

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure