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Gene expression from mouse models of B cell lymphomagenesis driven by gp130 signaling

ABSTRACT: This study examines the transcriptional changes invoked by activation of gp130 signaling in different mouse models of B cell lymphomagenesis. In order to study the in vivo effects of aberrant activity of IL-6/IL-6R/gp130-JAK/STAT3 signaling, we designed a transgene that allows conditional expression of L-gp130 by generating a ROSA26 knock-in mouse strain where compound L-gp130 and ZsGreen expression from the CAG promoter is prevented by a loxP- and a rox-flanked stop cassette. Total RNA extracted from purified B cells from young CD19Cre+/- ;L-gp130fl/+ and wildtype control mice was sequenced using unique molecular identifiers (UMI) in a paired end design where read1 corresponds to the cDNA and read2 contains the UMI. Furthermore, aging CD19Cre+/- ;L-gp130fl/+ animals developed tumors located predominantly in mesenteric lymph nodes. Infiltration of CD19;L-gp activated B cells was determined by Flow Cytometry and ZsGreen expression. Total RNA from tumors generally containing >60% ZsGreen+ cells was profiled as described above, for tumors with lower CD19;L-gp activated B cell content FACS was applied. In order to study the effects of activated IL-6/IL-6R/gp130-JAK/STAT3 signaling on Eµ-Myc-driven lymphomagenesis, CD19Cre;L-gp130fl;Eµ-Myc triple transgenic mice were generated and fetal liver hematopoietic stem/progenitor cell (FL-HSPC) grafts were transplanted into lethally irradiated syngeneic mice alongside FL-HSPC from CD19Cre;L-gp130f and Eµ-Myc control mice. Lastly, IL-6/IL-6R/gp130-JAK/STAT3 signaling was activated in the entire hematopoetic system using Vav1Cre resulting in Vav1Cre+/- ;L-gp130fl/+ animals. Independent of the time point of activation during hematopoietic and B cell differentiation, all Cre;L-gp compound mice succumbed to tumors of B cell origin.

ORGANISM(S): Mus musculus

PROVIDER: GSE132148 | GEO | 2019/06/06

REPOSITORIES: GEO

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Project description:Rheumatoid arthritis (RA) fibroblast‐like synoviocytes (FLS) derived from hip and knee have distinctive DNA methylation and transcriptome patterns in interleukin (IL)‐6 signaling and Janus kinase (JAK)–signal transducers and activators of transcription (STAT) pathways. To determine the functional effects of these joint‐specific signatures, we evaluated how RA hip and knee FLS differ in their response to IL‐6.Hip or knee RA FLS were obtained after arthroplasty. Previously published datasets on epigenetic landscape of FLS were mined to identify joint‐specific IL‐6–related epigenomic differences. RNA sequencing was performed on five RA hip and five knee FLS treated with or without IL‐6. Differential gene expression was determined using edgeR software. STAT3 phosphorylation was measured using bead assays. Sensitivity to tofacitinib was evaluated by measuring CCL2 inhibition using quantitative polymerase chain reaction. Assay for Transposase‐Accessible Chromatin sequencing and histone chromatin immunoprecipitation sequencing datasets from RA FLS were analyzed to identify epigenomic differences between hip and knee. Differential chromatin accessibility was associated with IL‐6, IL‐6R, and JAK1 genes. H3K27ac was also differentially marked at other JAK‐STAT–related genes, including STAT3‐STAT5A region. Principal component analysis of RNA sequencing data confirmed segregation between RA hip and knee FLS under basal conditions, that persisted following IL‐6 treatment. STAT3 phosphorylation after IL‐6 was significantly higher in knee than hip FLS and was highly correlated with JAK1 protein levels. Knee FLS were less sensitive to the JAK inhibitor tofacitinib than hip FLS. RA hip and knee FLS have distinct transcriptomes, epigenetic marks, and STAT3 activation patterns in the IL‐6 pathway. These joint‐specific differences might contribute to a differential clinical response in individual joints to targeted therapies such as JAK inhibitors.

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Gene expression from mouse models of B cell lymphomagenesis driven by gp130 signaling

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