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A dysregulated Acetyl/SUMO switch of FXR promotes hepatic inflammation in obesity

ABSTRACT: Acetylation of transcriptional regulators is normally dynamically regulated by nutrient status but is often persistently elevated in nutrient-excessive obesity conditions. We investigated the functional consequences of such aberrantly elevated acetylation of the nuclear receptor FXR as a model. Proteomic studies identified K217 as the FXR acetylation site in diet-induced obese mice. In vivo studies utilizing acetylation-mimic and -defective K217 mutants and gene expression profiling revealed that FXR acetylation increased proinflammatory gene expression, macrophage infiltration, and liver cytokine and triglyceride levels, impaired insulin signaling, and increased glucose intolerance. Mechanistically, acetylation of FXR blocked its interaction with the SUMO ligase PIASy and inhibited SUMO2 modification at K277, resulting in activation of inflammatory genes. SUMOylation of agonist-activated FXR increased its interaction with NF-κB but blocked that with RXRα, so that SUMO2-modified FXR was selectively recruited to and trans-repressed inflammatory genes without affecting FXR/RXRα target genes. A dysregulated Acetyl/SUMO switch of FXR in obesity may serve as a general mechanism for diminished anti-inflammatory response of other transcriptional regulators and provide potential therapeutic and diagnostic targets for obesity-related metabolic disorders.

ORGANISM(S): Mus musculus

PROVIDER: GSE62414 | GEO | 2014/10/17

SECONDARY ACCESSION(S): PRJNA264053

REPOSITORIES: GEO

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A dysregulated Acetyl/SUMO switch of FXR promotes hepatic inflammation in obesity

Project description:Acetylation of transcriptional regulators is normally dynamically regulated by nutrient status but is often persistently elevated in nutrient-excessive obesity conditions. We investigated the functional consequences of such aberrantly elevated acetylation of the nuclear receptor FXR as a model. Proteomic studies identified K217 as the FXR acetylation site in diet-induced obese mice. In vivo studies utilizing acetylation-mimic and -defective K217 mutants and gene expression profiling revealed that FXR acetylation increased proinflammatory gene expression, macrophage infiltration, and liver cytokine and triglyceride levels, impaired insulin signaling, and increased glucose intolerance. Mechanistically, acetylation of FXR blocked its interaction with the SUMO ligase PIASy and inhibited SUMO2 modification at K277, resulting in activation of inflammatory genes. SUMOylation of agonist-activated FXR increased its interaction with NF-κB but blocked that with RXRα, so that SUMO2-modified FXR was selectively recruited to and trans-repressed inflammatory genes without affecting FXR/RXRα target genes. A dysregulated Acetyl/SUMO switch of FXR in obesity may serve as a general mechanism for diminished anti-inflammatory response of other transcriptional regulators and provide potential therapeutic and diagnostic targets for obesity-related metabolic disorders. FXR-WT or the FXR-K217Q mutant was expressed in lean mice and FXR-WT or the FXR-K217R mutant was expressed in obese mice by adenoviral infection. One week after infection, mice were treated with GW4064 (30 mg/kg in corn oil) overnight before sacrifice and hepatic expression was analyzed by Illumina microarray.

2014-10-17 | E-GEOD-62414 | biostudies-arrayexpress

SUMO and RNAPolII chromatin profiling in SUMOylation-competent and -deficient bone marrow derived dendritic cells unstimulated or stimulated with LPS

Project description:Purpose: To determine SUMO1 and SUMO2 chromatin profile in a static and dynamic manner in BMDC before and after LPS stimulation, and to determine RNAPolII chromatin occupancy in sumoylation-deficient BMDC compared to wild-type cells. Methods: SUMO1, SUMO2 and RNAPolII chromatin profiles were determined by sequencing BMDC chromatin immunoprecipitated with antibodies specific for SUMO1, SUMO2 and RNAPolII before and after LPS stimulation. Results: We show dynamic occupancy of three distal sites upstream of Ifnb1 gene by SUMO1 and SUMO2, as well as increased RNAPolII recruitment on selected genes. Conclusions: SUMO acts as a regulator of inflammatory and anti-viral gene programs. A study of SUMO and RNAPolII chromatin profile in Bone Marrow derived Dendritic Cells.

2015-12-14 | E-GEOD-66315 | biostudies-arrayexpress

SUMO and RNAPolII chromatin profiling in SUMOylation-competent and -deficient bone marrow derived dendritic cells unstimulated or stimulated with LPS

2015-12-14 | GSE66315 | GEO

Effect of Sumo2 deletion on gene expression in the mouse brain

Project description:Mounting evidence indicates that small ubiquitin-like modifier (SUMO) conjugation regulates a wide range of neuronal functions and participates in learning and memory processes. Since many SUMO targets are transcription factors as well as other nuclear proteins modulating gene expression and SUMO2 is the predominant SUMO isoform, we aimed to identify how SUMO2 regualtes gene expression in the brain in order to better understand the role of SUMOylation in the brain fucntcion. In this study, we peformed RNA-Seq anaysis on hippocampus from SUMO2 conditional knockout mice.

2020-07-01 | GSE108196 | GEO

Ubc9 overexpression and SUMO1 deficiency blunt inflammation after intestinal ischemia/reperfusion.

Project description:The intestinal epithelium constitutes a crucial defense to the potentially life-threatening effects of gut microbiota. However, due to a complex underlying vasculature, hypoperfusion and resultant tissue ischemia pose a particular risk to function and integrity of the epithelium. The small ubiquitin-like modifier (SUMO) conjugation pathway critically regulates adaptive responses to metabolic stress and is of particular significance in the gut, as inducible knockout of the SUMO-conjugating enzyme Ubc9 results in rapid intestinal epithelial disintegration. Here we analyzed the pattern of individual SUMO isoforms in intestinal epithelium and investigated their roles in intestinal ischemia/reperfusion (I/R) damage. Immunostaining revealed that epithelial SUMO2/3 expression was almost exclusively limited to crypt epithelial nuclei in unchallenged mice. However, intestinal I/R or overexpression of Ubc9 caused a remarkable enhancement of epithelial SUMO2/3 staining along the crypt-villus axis. Unexpectedly, a similar pattern was found in SUMO1 knockout mice. Ubc9 transgenic mice, but also SUMO1 knockout mice were protected from I/R injury as evidenced by better preserved barrier function and blunted inflammatory responses. PCR array analysis of microdissected villus-tip epithelia revealed a specific epithelial contribution to reduced inflammatory responses in Ubc9 transgenic mice, as key chemotactic signaling molecules such as IL17A were significantly downregulated. Together, our data indicate a critical role particularly of the SUMO2/3 isoforms in modulating responses to I/R and provide the first evidence that SUMO1 deletion activates a compensatory process that protects from ischemic damage.

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FXR protects cisplatin-induced AKI via transcriptional regulation of ferroptosis.

Project description:Farnesoid X receptor (FXR, also known as NR1H4) is crucial to nephroprotective in several kinds of kidney diseases, including obesity, diabetes, aging, acute kidney injury and chronic kidney disease. FXR plays a key role in maintaining cholesterol and bile acid levels and is highly expressed in the liver, intestine and kidneys. In kidney diseases, it is reported that FXR has anti-lipogenic, anti‐inflammatory, antifibrotic, and antioxidant functions. Here, using genomics analysis, we investigated whether FXR attenuates cisplatin-induced AKI through the regulation of ferroptosis. The increased blood urea nitrogen, serum creatinine and ferroptotic responses in cisplatin-induced AKI mice were attenuated by treatment with FXR agonist, GW4064, while those were exacerbated in FXR knockout mice. Using RNA-sequencing analysis, we found novel target genes for FXR associated with ferroptosis. FXR agonist treatment increases lipid and glutathione metabolic gene expression and decreases cell death genes expression. This study identifies transcriptional regulation of ferroptosis by FXR as a potential therapeutic target for cisplatin-induced AKI.

2022-07-06 | GSE193860 | GEO

Genome wide occupancy of SUMO machinery in proliferative and Ras-induced senescent human primary fibroblasts

Project description:Transcription factors represent one of the largest groups of proteins regulated by SUMO, and their modification has generally been correlated with transcriptional repression. However, as most of the studies focus on specific sumoylated transcriptional regulators, the distribution and global role of SUMO on chromatin in relation to transcription regulation remain largely unknown. To investigate this role, we determined the occupancy of SUMO machinery proteins on chromatin by ChIP coupled to sequencing in human primary cells. Examination of 3 histone modifications, Polymerase II, SUMO1, SUMO2, Ubc9 and PIASy in proliferative and Ras-induced senescent fibroblasts.

2013-07-24 | E-GEOD-42211 | biostudies-arrayexpress

Mus musculus

Project description:A dysregulated Acetyl/SUMO switch of FXR promotes hepatic inflammation in obesity

| PRJNA264053 | ENA

Heat shock-induced changes in chromatin binding of SUMO2/3 modified proteins

2015-07-02 | GSE66448 | GEO

Heat shock-induced changes in chromatin binding of SUMO2/3 modified proteins

Project description:Heat shock induces rapid modification of proteins with SUMO2/3. This study concentrated in charaterizing how these changes are reflected on SUMOylation of chromatin bound proteins, trancsription, and chromatin binding of SUMO ligase PIAS1. Comparison of chromatin SUMO2/3 modification pattern in non-stressed and heat shocked K562 and VCaP cells. All samples were done as biological replicates. In K562 cells, SUMO2/3 ChIP-seq was done in non-stressed (37C) and heat shocked (30min at 43C) cells. The effect of heat shock factor 1 (HSF1) to chromatin SUMOylation in HS was studied in HSF1 silenced (shHSF1) K562 cells (non-stressed vs. heat shocked) using scramble shRNA transfected cells as control (shSCR). SUMO2/3, SUMO ligase PIAS1,and RNA polymerase II binding in HS (30 min at 43C) and recovery from HS (1h at 37C after HS) was studied using ChIP-seq. Effect of PIAS1 for chromatin SUMOylation was studied in PIAS1 silenced (siRNA for PIAS1, siPIAS1) cells (non-stressed or heat shocked) using non-targeting siRNA transfected cells as a control (siNON). Effect of SUMOylation to chromatin binding of RNA polymerase II was studied in UBE2I silenced (siRNA for UBE2I) and control (non-targeting siRNA transfected, siNON) VCaP cells (non-stressed or heat shocked). Effect of transtription inhibition for chromatin SUMOylation was studied in TRP (triptolide; 1 micromolar, 3h) and DRB (5,6-Dichlorobenzimidazole 1-beta-D-ribofuranosidase; 100 micromolar, 3h) treated VCaP cells. GRO-seq was used to determine HS-induced changes in nascent transcription in K562 cells.

2015-07-02 | E-GEOD-66448 | biostudies-arrayexpress

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