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Single cell RNA sequencing of cells isolated from the intestinal crypts of mice bearing epithelial cell-specific Ptger4 ablation (Drop-seq)

ABSTRACT: Crypts isolated from the small intestine of mice bearing epithelial cell-specific ablation of the Ptger4 gene (VillinCrePtger4flox, "V") and normal littermate control mice (Ptger4flox, "F") were dissociated into single cell suspensions and subjected to the Drop-seq protocol. N = 2 mice per genotype were independently processed as biological replicates (V1, V2 and F1, F2). A total of three Drop-seq collections (samples) were processed for each genotype, two from the first biological replicate (V1A, V1B, F1A, F1B) and one from the second biological replicate (V2, F2).

ORGANISM(S): Mus musculus

PROVIDER: GSE142418 | GEO | 2019/12/21

REPOSITORIES: GEO

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Project description:Recognition of foreign antigens by B cell receptor (BCR) on mature B cells leads to their clonal expansion, which is critically important for the effective host defence of the organism. However, excessive antigenic responses or reaction of B cells against bodyâs own components frequently lead to diverse immune diseases, such as B-cell lymphoma or autoimmunity, that often affect humans. Identification of genes that restrain uncontrolled proliferation of B cells is therefore an important goal towards understanding the origin of such diseases. Here we identify Ptger4 as a negative feedback regulator of B-cell proliferation in response to BCR triggering, and show that its encoded EP4 receptor is a principal molecule conveying the growth-suppressive effect of prostaglandin E2 (PGE2). In controlled in vitro assays, Ptger4-/- B cells showed augmented proliferative response and increased expression of activating genes upon BCR stimulation. Stable knock-down of Ptger4 in B-cell lymphoma markedly accelerated tumour spread in mice, while Ptger4 overexpression yielded significant protection. Lack of Ptger4 rendered mouse B cells completely resistant to proliferation arrest signalled by PGE2, and we find by transcriptional profiling that intrinsic activity of Ptger4 and PGE2-EP4 signalling target a similar set of activating genes. We further show that Ptger4 inhibits mouse B-cell activation in vivo and find it significantly downregulated in human B-cell lymphoma. Our results demonstrate that Ptger4 functions in B cells as a candidate tumour suppressor whose activity is regulated by the presence of PGE2 in the microenvironment. These findings suggest that targeting EP4 receptor for prostaglandin may present a novel strategy for treatment of B-cell diseases. Keywords: time course, cell type comparison, compound treatment design, microarray experiment record B cells were extracted from spleen of Ptger4+/+ and Ptger4-/- mice, and incubated in vitro for the indicated period with or without anti-IgM (Fab')2 antibody fragments and co-treated with or without PGE2. Total RNA was extracted, amplified, labelled with Cy3 or Cy5, and hybridized to mouse 24k oligo-arrays using a dye-swap strategy.

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Single cell RNA sequencing of cells isolated from the intestinal crypts of mice bearing epithelial cell-specific Ptger4 ablation (Drop-seq)

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