Inflammatory Cytokines Stabilize SOXC Transcription Factors to Mediate the Transformation of Fibroblast‐Like Synoviocytes in Arthritic Disease

Bhattaram, Pallavi; Muschler, George F.; Wixler, Viktor; Lefebvre, Véronique

doi:10.1002/art.40386

Cited by 26 publications

(33 citation statements)

References 49 publications

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“…In addition, our results indicate that Sox4 expression in hepatocytes could be regulated by glucose, palmitate, and insulin. Recent studies identified Sox4 as a downstream target of inflammatory cytokines (43,44). Therefore, whether chronic and persistent inflammation in obesity contributes to the upregulation of Sox4 remains to be addressed.…”

Section: Discussionmentioning

confidence: 99%

SRY-Box Containing Gene 4 Promotes Liver Steatosis by Upregulation of SREBP-1c

et al. 2018

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Obesity is usually associated with an increased risk of nonalcoholic fatty liver disease that is characterized by accumulation of excessive triglyceride (TG) in hepatocytes. However, the factors involved in the obesity-induced hepatosteatosis are poorly defined. Here, we report that SRY-box containing gene 4 (), a transcription factor that regulates cell proliferation and differentiation, plays an important role in hepatic TG metabolism. expression levels are markedly upregulated in livers of obese rodents and humans. Adenovirus-medicated overexpression of in the livers of lean mice promotes liver steatosis, whereas liver-specific knockdown of ameliorates TG accumulation and improves insulin resistance in obese mice. At the molecular level, we show that could directly control the transcription of gene through binding to its proximal promoter region. Thus, we have identified as an important component of hepatic TG metabolism.

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Section: Discussionmentioning

confidence: 99%

SRY-Box Containing Gene 4 Promotes Liver Steatosis by Upregulation of SREBP-1c

et al. 2018

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“…There is little doubt, however, that these proteins are subjected to posttranslational regulation. Supporting this concept, inhibition of SOXC proteasomal degradation was proposed as a major mechanism whereby inflammatory cytokines mediate synovial fibroblast transformation in arthritis (Bhattaram, Muschler, Wixler, & Lefebvre, 2018). A post-translational mechanism was postulated but remains to be identified.…”

Section: Post-translational Regulation Of Sox Proteins In Skeletal Cellsmentioning

confidence: 99%

Roles and regulation of SOX transcription factors in skeletogenesis

Lefebvre

2019

Current Topics in Developmental Biology

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SOX transcription factors participate in the specification, differentiation and activities of many cell types in development and beyond. The 20 mammalian family members are distributed into eight groups based on sequence identity, and while co-expressed same-group proteins often have redundant functions, different-group proteins typically have distinct functions. More than a handful of SOX proteins have pivotal roles in skeletogenesis. Heterozygous mutations in their genes cause human diseases, in which skeletal dysmorphism is a major feature, such as campomelic dysplasia (SOX9), or a minor feature, such as LAMSHF syndrome (SOX5) and Coffin-Siris-like syndromes (SOX4 and SOX11). Loss-and gain-of-function experiments in animal models have revealed that SOX4 and SOX11 (SOXC group) promote skeletal progenitor survival and control skeleton patterning and growth; SOX8 (SOXE group) delays the differentiation of osteoblast progenitors; SOX9 (SOXE group) is essential for chondrocyte fate maintenance and differentiation, and works in cooperation with SOX5 and SOX6 (SOXD group) and other types of transcription factors. These and other SOX proteins have also been proposed, mainly through in vitro experiments, to have key roles in other aspects of skeletogenesis, such as SOX2 in osteoblast stem cell self-renewal. We here review current knowledge of well-established and proposed skeletogenic roles of SOX proteins, their transcriptional and non-transcriptional actions, and their modes of regulation at the gene, RNA and protein levels. We also discuss gaps in knowledge and directions for future research to further decipher mechanisms underlying skeletogenesis in health and diseases and identify treatment options for skeletal malformation and degeneration diseases.

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“…The institutional animal care and use committee (IACUC) at Emory University approved animal husbandry and experimental procedures. FLS were isolated by digesting interphalangeal joint synovium according to previously described protocol (11). Hind paws from wild-type mice with a C57/B6 background were deskinned, followed by digestion with 1mg/ml collagenase IV (Sigma-Aldrich) for 2h at 37°C under sterile conditions (35).…”

Section: Methodsmentioning

confidence: 99%

“…The inflammatory milieu in RA synovium promotes an abnormal epigenetic landscape, modulates chromatin accessibility and favors the pathogenic processes observed in RA FLS such as invasion, migration and production of proinflammatory mediators (1,8,9). The vital role of tumor necrosis factoralpha (TNF) in triggering and maintaining an aggressive FLS phenotype has been well documented both in the in vivo and in vitro studies (10)(11)(12)(13). Hence, manipulating TNFinduced sustained chromatin activation in RA FLS represent a treatment opportunity that might aid in combating RA persistence and therapeutic resistance.…”

Section: Introductionmentioning

confidence: 99%

Chronic exposure to TNF reprograms cell signaling pathways in fibroblast-like synoviocytes by establishing long-term inflammatory memory

Gangishetti

Ramírez-Pérez

Jones

et al. 2020

Preprint

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Fibroblast-like synoviocytes (FLS) play a critical role in the pathogenesis of rheumatoid arthritis (RA). Chronic inflammation induces transcriptomic and epigenetic modifications that imparts a persistent catabolic phenotype to the FLS, despite their dissociation from the inflammatory environment. We analyzed high throughput gene expression and chromatin accessibility data from human and mouse FLS from our and other studies available on public repositories, with the goal of identifying the persistently reprogrammed signaling pathways driven by chronic inflammation. We found that the gene expression changes induced by short-term tumor necrosis factor-alpha (TNF) treatment were largely sustained in the FLS exposed to chronic inflammation. These changes that included both activation and repression of gene expression, were accompanied by the remodeling of chromatin accessibility. The sustained activated genes (SAGs) included established proinflammatory signaling components known to act at multiple levels of NF-kappaB, STAT and AP-1 signaling cascades. Interestingly, the sustained repressed genes (SRGs) included critical mediators and targets of the BMP signaling pathway. We thus identified sustained repression of BMP signaling as a unique constituent of the long-term inflammatory memory induced by chronic inflammation. We postulate that simultaneous targeting of these activated and repressed signaling pathways may be necessary to combat RA persistence. on a Hi-Seq 2500 System (University of Georgia Genomics Core) to generate data in FastQ file format. In order to study chromatin accessibility changes due to chronic inflammation, we downloaded FastQ files from a DNase I hypersensitivity sequencing (DNase-seq) experiment of wild-type FLS and inflamed FLS from inflammatory arthritis mouse model (Table S1). FastQ files from the ATAC-seq and DNase-seq experiments were analyzed using the Strand NGS sequence analysis pipeline first by aligning the sequences to the mouse genome, mm10 build, followed by removal of duplicate reads.Peak calling and gene annotation were performed by MACS2 algorithm using a padding distance of 5 kb from the transcription start sites of genes. Pathway analysis. Ingenuity Pathway Analysis tool was used to predict the canonical regulatory pathways and diseases and functions associated with the SAGs and SRGs (38). Functional protein-protein analysis was performed using STRING protein-protein interaction plugin on Cytoscape, an open source software platform for visualizing complex networks pathway analysis tool (39, 40). Open-source tool, ChEA3 that uses ChIP-seq experiments from the ENCODE database was used to predict transcription factors associations with SAG and SRGs (17).

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Inflammatory Cytokines Stabilize SOXC Transcription Factors to Mediate the Transformation of Fibroblast‐Like Synoviocytes in Arthritic Disease

Cited by 26 publications

References 49 publications

SRY-Box Containing Gene 4 Promotes Liver Steatosis by Upregulation of SREBP-1c

SRY-Box Containing Gene 4 Promotes Liver Steatosis by Upregulation of SREBP-1c

Roles and regulation of SOX transcription factors in skeletogenesis

Chronic exposure to TNF reprograms cell signaling pathways in fibroblast-like synoviocytes by establishing long-term inflammatory memory

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