COUP-TFII revisited: Its role in metabolic gene regulation

Ashraf, Usman; Sánchez, Edwin R.; Kumarasamy, Sivarajan

doi:10.1016/j.steroids.2018.11.013

Cited by 24 publications

(24 citation statements)

References 74 publications

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“…Next and telomeric to NR2F2-AS1 is the NR2F2 gene, which is transcribed from centromere to telomere and in which alternate splicing results in multiple transcript variants (https://www.ncbi.nlm.nih.gov/gene/7026). NR2F2 codes for a member of the steroid thyroid hormone superfamily of nuclear receptors, a ligand-inducible transcription factor involved in the regulation of many different genes (31,32). A possible consequence of the t(X;15)(q22;q26) might also be deregulation of NR2F2 in a manner similar to that which occurs with the fusion of the collagen type I alpha 1 chain gene (COL1A1) with the plateletderived growth factor subunit B gene (PDFGB) , the ubiquitin specific peptidase 6 gene (USP6), and FYN proto-oncogene, Src family tyrosine kinase gene (FYN) in dermatofibrosarcoma protuberans, aneurysmal bone cyst, and epithelioid osteoblastoma, respectively (33)(34)(35)(36)(37).…”

Section: Discussionmentioning

confidence: 99%

Fusion of the COL4A5 Gene With NR2F2-AS1 in a Hemangioma Carrying a t(X;15)(q22;q26) Chromosomal Translocation

Panagopoulos

Gorunova

Lobmaier

et al. 2020

Cancer Genomics Proteomics

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Background/Aim: Hemangiomas are benign neoplastic proliferations of blood vessels. Cytogenetic information on hemangiomas is limited to four tumors with abnormal karyotypes. We report here a solitary chromosomal translocation and its molecular consequence in a hemangioma. Materials and Methods: A cavernous hemangioma was extirpated from the foot of a 62 years old man and genetically studied with cytogenetic and molecular genetic methodologies. Results: G-Banding analysis of short-term cultured tumor cells yielded the karyotype 46,Y,t(X;15)(q22;q26)[4]/46,XY[12]. RNA sequencing detected fusion of the collagen type IV alpha 5 chain gene (COL4A5 on Xq22.3) with intronic sequences of nuclear receptor subfamily 2 group F member 2 antisense RNA 1 (NR2F2-AS1 on 15q26.2) resulting in a putative COL4A5 truncated protein. The fusion was verified by RT-PCR together with Sanger sequencing and FISH analyses. Conclusion: The involvement of COL4A5 indicates that some hemangiomas have pathogenetic similarities with other benign tumors such as leiomyomas and subungual exostosis. Hemangiomas are benign neoplastic proliferations of blood vessels that may develop in any vascularized tissue. Histologically, they are composed of multiple vascular channels lined with a single layer of endothelium and supported by a fibrous connective tissue scaffold (1). They occur most often in the skin or subcutaneous tissue but may also be found in skeletal muscle, bone, kidneys, lungs, colon, brain, spleen, liver, and pancreas (2-5). Hemangiomas are mostly solitary although multiple hemangioma lesions may occur in individual patients (1). The incidence and prevalence of hemangiomas are difficult to calculate since most lesions are small and asymptomatic. There are several clinical and histological subtypes (6-9). In the present study, we report the genomic abnormalities of a cavernous hemangioma. Ethics statement. The study was approved by the Regional Ethics Committee (Regional komité for medisinsk forskningsetikk Sør-Øst, Norge, http://helseforskning. etikkom.no, 2010/1389/REK sør-øst A). Written informed consent was obtained from the patient. The Ethics Committee's approval included a review of the consent procedure. All patient information has been de-identified.

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Section: Discussionmentioning

confidence: 99%

Fusion of the COL4A5 Gene With NR2F2-AS1 in a Hemangioma Carrying a t(X;15)(q22;q26) Chromosomal Translocation

Panagopoulos

Gorunova

Lobmaier

et al. 2020

Cancer Genomics Proteomics

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“…Giving the important role of COUP-TFII on glucose and lipid metabolism (Ashraf et al, 2019), we hypothesized that COUP-TFII might regulate myofibroblast differentiation through metabolism reprogramming. Our proteomic data revealed that COUP-TFII promotes the expression of proteins enriched in metabolic process critical for myofibroblasts, in particular, suppression of FAO and enhancement of glycolysis.…”

Section: Discussionmentioning

confidence: 99%

“…Chicken ovalbumin upstream promoter-transcription Factor II (COUP-TFII, also known as NR2F2) is an orphan member of the nuclear receptor family with unknown endogenous ligands (Pereira, Qiu et al, 1999). Since COUP-TFII has been reported to regulate metabolic functions (Ashraf, Sanchez et al, 2019, Li, Xie et al, 2009, Planchais, Boutant et al, 2015, we evaluated whether it played an important role in fibrosis. Downstream proteins under COUP-TFII control tend to be involved in energy production, anabolic pathways, and cell cycle progression, all of which impact on cell proliferation , Planchais et al, 2015, Wu, Kao et al, 2015.…”

Section: Introductionmentioning

confidence: 99%

Orphan nuclear receptor COUP-TFII drives the myofibroblast metabolic shift leading to fibrosis

Galichon

Xiao

et al. 2020

Preprint

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Recent studies demonstrated that metabolic disturbance, such as augmented glycolysis, contributes to fibrosis. The molecular regulation of this metabolic perturbation in fibrosis, however, has been elusive. COUP-TFII (also known as NR2F2) is an important regulator of glucose and lipid metabolism. Its contribution to organ fibrosis is undefined. Here, we found increased COUP-TFII expression in myofibroblasts in kidneys of patients with chronic kidney disease, fibrotic lungs of patients with idiopathic pulmonary fibrosis, fibrotic human kidney organoids, and fibrotic mouse kidneys after injury. Genetic ablation of COUP-TFII in mice resulted in attenuation of injury-induced kidney fibrosis. A non-biased proteomic study revealed the suppression of fatty acid oxidation and the enhancement of glycolysis pathways in COUP-TFII overexpressing fibroblasts. Overexpression of COUP-TFII in fibroblasts was sufficient to enhance glycolysis and increase alpha smooth muscle actin (αSMA) and collagen1 levels. Knockout of COUP-TFII decreased glycolysis and collagen1 levels in fibroblasts. Chip-qPCR assays revealed the binding of COUP-TFII on the promoter of PGC1α, a critical regulator of mitochondrial genesis and oxidative metabolism. Overexpression of COUP-TFII reduced the cellular level of PGC1α. In conclusion, COUP-TFII mediates fibrosis by serving as a key regulator of the shift in cellular metabolism of interstitial pericytes/fibroblasts from oxidative respiration to aerobic glycolysis. The fibrogenic response may share a common pathway in different organ injury and failure. Targeting COUP-TFII serves as a novel treatment approach for mitigating fibrosis in chronic kidney disease and potential other organ fibrosis.

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“…The copyright holder for this preprint this version posted June 18, 2021. ; https://doi.org/10.1101/2021.06.18.448955 doi: bioRxiv preprint but can involve more complex interactions such as heterodimerization with COUP-TFs and RXR. Specifically, HNF4α co-interaction with COUP-TFII elicits tissue-specific inhibitory and synergistic gene expression effects (Ashraf et al, 2019). Alternatively, COUP-TFII dimerizes with RXR and competes with HNF4α/RXR for the same binding site or sequesters RXR thereby limiting HNF4α/RXR signaling events (Ashraf et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

“…Specifically, HNF4α co-interaction with COUP-TFII elicits tissue-specific inhibitory and synergistic gene expression effects (Ashraf et al, 2019). Alternatively, COUP-TFII dimerizes with RXR and competes with HNF4α/RXR for the same binding site or sequesters RXR thereby limiting HNF4α/RXR signaling events (Ashraf et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Genome-wide ChIPseq analysis of AhR, COUP-TF, and HNF4 enrichment in TCDD-treated mouse liver

Nault

2021

Preprint

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The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor known for mediating the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds. Although the canonical mechanism of AhR activation involves heterodimerization with the aryl hydrocarbon receptor nuclear translocator, other transcriptional regulators that interact with AhR have been identified. Enrichment analysis of motifs in AhR-bound genomic regions implicated co-operation with COUP transcription factor (COUP-TF) and hepatocyte nuclear factor 4 (HNF4). The present study investigated AhR, HNF4α and COUP-TFII genomic binding and effects on gene expression associated with liver-specific function and cell differentiation in response to TCDD. Hepatic ChIPseq data from male C57BL/6 mice at 2 hrs after oral gavage with 30 μg/kg TCDD were integrated with bulk RNA-sequencing (RNAseq) time-course (2 - 72 hrs) and dose-response (0.01 - 30 μg/kg) datasets to assess putative AhR, HNF4α and COUP-TFII interactions associated with differential gene expression. TCDD treatment resulted in the genomic enrichment of 23,701, 11,688, and 9,547 binding regions for AhR, COUP-TFII and HNF4α, respectively, throughout the genome. Functional enrichment analysis of differentially expressed genes (DEGs) identified differential binding enrichment for AhR, COUP-TFII, and HNF4a to regions within liver-specific genes suggesting intersections associated with the loss of liver-specific functions and hepatocyte differentiation. Analysis found that the repression of liver-specific, HNF4α target and hepatocyte differentiation genes, involved increased AhR and HNF4α binding with decreased COUP-TFII binding. Collectively, these results suggested TCDD-elicited loss of liver-specific functions and markers of hepatocyte differentiation involved interactions between AhR, COUP-TFII and HNF4α.

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COUP-TFII revisited: Its role in metabolic gene regulation

Cited by 24 publications

References 74 publications

Fusion of the COL4A5 Gene With NR2F2-AS1 in a Hemangioma Carrying a t(X;15)(q22;q26) Chromosomal Translocation

Fusion of the COL4A5 Gene With NR2F2-AS1 in a Hemangioma Carrying a t(X;15)(q22;q26) Chromosomal Translocation

Orphan nuclear receptor COUP-TFII drives the myofibroblast metabolic shift leading to fibrosis

Genome-wide ChIPseq analysis of AhR, COUP-TF, and HNF4 enrichment in TCDD-treated mouse liver

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