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KMT2D Links TGF-β Signalling to Non-Canonical Activin Pathway and Regulates Pancreatic Cancer Cell Plasticity

ABSTRACT: KMT2D Links TGF-β Signalling to Non-Canonical Activin Pathway and Regulates Pancreatic Cancer Cell Plasticity

PROVIDER: PRJNA821829 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18557885.fastq.gz	Fastqsanger.gz
	SRR18557886.fastq.gz	Fastqsanger.gz
	SRR18557887.fastq.gz	Fastqsanger.gz
	SRR18557888.fastq.gz	Fastqsanger.gz
	SRR18557889.fastq.gz	Fastqsanger.gz

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Project description:Background The striking association of HLA-B27 with spondyloarthritis (SpA) has been known for 50 years. However, its pathophysiological significance remains incompletely understood. In the HLA-B27/human-β2 microglobulin (hβ2m) transgenic rat (B27 rat) that spontaneously develops inflammatory phenotype characteristic of SpA, myeloid cells expressing the HLA-B27/h2m transgene are critical for disease induction and functionally impaired. Recently, we produced HLA-B27/hβ2m transgenic Drosophila to study non-canonical effects of HLA-B27. We showed that HLA-B27/h2m expressed in Drosophila wing imaginal disc deregulated BMP pathway by interacting physically with the type I bone morphogenetic protein (BMP) receptor (BMPR1) Saxophone (Sax), leading to a loss of crossveins. Methods Genetic interaction was studied between the activin/TGF pathway and HLA-B27/hβ2m in transgenic Drosophila wings. The HLA-B27-bound peptidome was characterized in wing imaginal discs from transgenic Drosophila by high-performance liquid chromatography and mass spectrometry of the peptide fraction eluted from affinity purified HLA-B27. In mesenteric lymph node (mLN) T cells from B27 rats, physical interaction between HLA-B27 and activin receptor-like kinase-2 (ALK2), ALK3 and ALK5 BMPR1s was assessed by proximity ligation assay and phosphorylation of SMADs and proteins of the non-canonical BMP/TGF pathway induced by its ligands was assessed by flow cytometry. Transcript level of several target genes of the TGF pathway was evaluated by real-time quantitative polymerase chain reaction in mLN subsets of T cells from B27 and control nontransgenic rats, with and without treatment by TGF. Results We showed that, in addition to the BMP pathway, inappropriate signaling through the activin/transforming growth factor β (TGFβ) pathway, involving Baboon (Babo) BMPR1, also contributed to the crossveinless wing phenotype. We identified a set of peptides bound to HLA-B27 with canonical binding motif in HLA-B27/hβ2m transgenic Drosophila wing imaginal disc, despite the lack of peptide loading complex. We then demonstrated specific physical interaction, between HLA-B27/h2m and both mammalian orthologues of Sax and Babo, i.e. ALK2 and ALK5 (i.e. TGF receptor I), in the mLN cells from B27 rat. The magnitude of phosphorylation of SMAD2/3 in response to TGFβ1 was increased in T cells from adult and premorbid B27 rats, showing evidence for deregulated TGF pathway. Accordingly, expression of several target genes of the pathway was increased in T cells from B27 rats, in basal conditions and/or after TGFexposure, including Foxp3, Rorc, Runx1 and Maf. Interestingly. Tgfb1 expression was reduced in naïve T cells from B27 rats, even premorbid, an observation consistent with a pro-inflammatory pattern. Conclusions This study highlights a complex interplay between HLA-B27 and the BMP/TGFβ pathways in both Drosophila and B27 rat. Given the importance of the TGF pathway in CD4+ T cells differenciation and regulation, the disturbance caused by HLA-B27 could contribute to the abnormal expansion of pro-inflammatory T helper 17 cells and the altered regulatory T cell phenotype observed in B27 rat.

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KMT2D Links TGF-β Signalling to Non-Canonical Activin Pathway and Regulates Pancreatic Cancer Cell Plasticity

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