Hepatic IRF2BP2 Mitigates Nonalcoholic Fatty Liver Disease by Directly Repressing the Transcription of ATF3

Fang, Jing; Ji, Yan‐Xiao; Zhang, Peng; Cheng, Lin; Chen, Yue; Chen, Jun; Su, Yi; Xu, Cheng; Zhang, Yan; Li, Tianyu; Zhu, Xiashi; Zhang, Xiaojing; Wei, Xiang

doi:10.1002/hep.30950

Cited by 24 publications

(16 citation statements)

References 41 publications

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“…The ChIP assay was performed using established protocols as previously described [ 62 ]. SK-N-BE (2) cells were seeded into T75 and divided into two groups, the treatment group was treated with 10 nM of GNE987 for 24 h, while the control group was treated with the same volume of solvent for the same time.…”

Section: Methodsmentioning

confidence: 99%

BRD4 inhibitor GNE987 exerts anti-cancer effects by targeting super-enhancers in neuroblastoma

Chen

et al. 2022

Cell Biosci

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Background Neuroblastoma (NB) is a common extracranial malignancy with high mortality in children. Recently, super-enhancers (SEs) have been reported to play a critical role in the tumorigenesis and development of NB via regulating a wide range of oncogenes Thus, the synthesis and identification of chemical inhibitors specifically targeting SEs are of great urgency for the clinical therapy of NB. This study aimed to characterize the activity of the SEs inhibitor GNE987, which targets BRD4, in NB. Results In this study, we found that nanomolar concentrations of GNE987 markedly diminished NB cell proliferation and survival via degrading BRD4. Meanwhile, GNE987 significantly induced NB cell apoptosis and cell cycle arrest. Consistent with in vitro results, GNE987 administration (0.25 mg/kg) markedly decreased the tumor size in the xenograft model, with less toxicity, and induced similar BRD4 protein degradation to that observed in vitro. Mechanically, GNE987 led to significant downregulation of hallmark genes associated with MYC and the global disruption of the SEs landscape in NB cells. Moreover, a novel candidate oncogenic transcript, FAM163A, was identified through analysis of the RNA-seq and ChIP-seq data. FAM163A is abnormally transcribed by SEs, playing an important role in NB occurrence and development. Conclusion GNE987 destroyed the abnormal transcriptional regulation of oncogenes in NB by downregulating BRD4, which could be a potential therapeutic candidate for NB.

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Section: Methodsmentioning

confidence: 99%

BRD4 inhibitor GNE987 exerts anti-cancer effects by targeting super-enhancers in neuroblastoma

Chen

et al. 2022

Cell Biosci

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“…To validate a second candidate, we also confirmed binding of IRF2BP1 and IRF2BP2 to the proximal promoter of human ATF3 in HeLa cells ( Fig EV2). ATF3 was a particularly promising candidate, because it had just been found to be under direct control of IRF2BP2 in mouse nonalcoholic fatty liver (Fang et al, 2020). We next wanted to interrogate whether transient deSUMOylation of IRF2BP proteins regulates its association with the DUSP1 promoter.…”

Section: Sumoylation-deficient Irf2bp1 Cells Differ In Egf-dependent mentioning

confidence: 99%

Transient deSUMOylation of IRF2BP proteins controls early transcription in EGFR signaling

et al. 2021

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Molecular switches are essential modules in signaling networks and transcriptional reprogramming. Here, we describe a role for small ubiquitin‐related modifier SUMO as a molecular switch in epidermal growth factor receptor (EGFR) signaling. Using quantitative mass spectrometry, we compare the endogenous SUMO proteomes of HeLa cells before and after EGF stimulation. Thereby, we identify a small group of transcriptional coregulators including IRF2BP1, IRF2BP2, and IRF2BPL as novel players in EGFR signaling. Comparison of cells expressing wild type or SUMOylation‐deficient IRF2BP1 indicates that transient deSUMOylation of IRF2BP proteins is important for appropriate expression of immediate early genes including dual specificity phosphatase 1 (DUSP1, MKP‐1) and the transcription factor ATF3. We find that IRF2BP1 is a repressor, whose transient deSUMOylation on the DUSP1 promoter allows—and whose timely reSUMOylation restricts—DUSP1 transcription. Our work thus provides a paradigm how comparative SUMO proteome analyses serve to reveal novel regulators in signal transduction and transcription.

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“…ELAVL1 also protects against non-alcoholic fatty liver disease (NAFLD) ( 55 ), a condition that associates with increased risk of coronary artery calcification ( 56 ). NAFLD is made worse by ablation of Irf2bp2 in the mouse ( 57 ). Together with recent work tying ELAVL1 in mediating the pro-atherosclerosis effect of a macrophage-specific lncRNA ( 24 ), these studies point to an interesting parallel that may contribute to arterial calcification mediated through ELAVL1 modulation of IRF2BP2.…”

Section: Discussionmentioning

confidence: 99%

IRF2BP2 3′UTR Polymorphism Increases Coronary Artery Calcification in Men

Vilmundarson

Duong

Soheili

et al. 2021

Front. Cardiovasc. Med.

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Interferon regulatory factor 2 binding protein 2 (IRF2BP2) suppresses the innate inflammatory response of macrophages. A 9-nucleotide deletion (rs3045215) in the 3′ untranslated region (3′-UTR) of human IRF2BP2 mRNA confers risk of coronary artery disease (CAD) in the Ottawa Heart Genomics Study (OHGS). Here, we sought to identify regulatory mechanisms that may contribute to this risk. We tested how lipopolysaccharides (LPS) affects IRF2BP2 expression in human THP-1 macrophages and primary aortic smooth muscle cells (HAoSMC) genotyped for the deletion allele. Both cell types are implicated in coronary atherosclerosis. We also examined how the deletion affects interaction with RNA binding proteins (RBPs) to regulate IRF2BP2 expression. LPS altered allele-specific binding of RBPs in RNA gel shift assays with the THP-1 macrophage protein extracts. The RBP ELAVL1 suppressed the expression of a luciferase reporter carrying the 3′UTR of IRF2BP2 with the deletion allele. Other RBPs AUF1 or KHSRP did not confer such allele specific regulation. Since it is co-inherited with a risk variant for osteoporosis, a condition tied to arterial calcification, we examined the association of the deletion allele with coronary artery calcification in individuals who had undergone computed tomography angiography in the OHGS. In 323 individuals with a minimal burden of atherosclerosis (<30% coronary stenosis) and 138 CAD cases (>50% stenosis), Mendelian randomization revealed that the rs3045215 deletion allele significantly increased coronary artery calcification in men with minimal coronary stenosis. Thus, not only does the rs3045215 deletion allele predict atherosclerosis, but it also predisposes to early-onset calcification in men.

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Hepatic IRF2BP2 Mitigates Nonalcoholic Fatty Liver Disease by Directly Repressing the Transcription of ATF3

Cited by 24 publications

References 41 publications

BRD4 inhibitor GNE987 exerts anti-cancer effects by targeting super-enhancers in neuroblastoma

BRD4 inhibitor GNE987 exerts anti-cancer effects by targeting super-enhancers in neuroblastoma

Transient deSUMOylation of IRF2BP proteins controls early transcription in EGFR signaling

IRF2BP2 3′UTR Polymorphism Increases Coronary Artery Calcification in Men

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