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Transcriptomic Remodelling of Fetal Endothelial Cells During Establishment of Inflammatory Memory.

ABSTRACT: Inflammatory memory involves the molecular and cellular 'reprogramming' of innate immune cells following exogenous stimuli, leading to non-specific protection against subsequent pathogen exposure. This phenomenon has now also been described in non-hematopoietic cells, such as human fetal and adult endothelial cells. In this study we mapped the cell-specific DNA methylation profile and the transcriptomic remodelling during the establishment of inflammatory memory in two distinct fetal endothelial cell types - a progenitor cell (ECFC) and a differentiated cell (HUVEC) population. We show that both cell types have a core transcriptional response to an initial exposure to a viral-like ligand, Poly(I:C), characterised by interferon responsive genes. There was also an ECFC specific response, marked by the transcription factor ELF1, suggesting a non-canonical viral response pathway in progenitor endothelial cells. Next, we show that both ECFCs and HUVECs establish memory in response to an initial viral exposure, resulting in an altered subsequent response to lipopolysaccharide. While the capacity to train or tolerize the induction of specific sets of genes was similar between the two cell types, the progenitor ECFCs show a higher capacity to establish memory. Among tolerized cellular pathways are those involved in endothelial barrier establishment and leukocyte migration, both important for regulating systemic immune-endothelial cell interactions. These findings suggest that the capacity for inflammatory memory may be a common trait across different endothelial cell types but also indicate that the specific downstream targets may vary by developmental stage.

SUBMITTER: Weiss E

PROVIDER: S-EPMC8640490 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Preeclampsia impairs fetoplacental vascular function and increases risks of adult-onset cardiovascular disorders in children born to preeclamptic mothers, implicating that preeclampsia programs fetal vasculature in utero. However, the underlying mechanisms remain elusive. We hypothesize that preeclampsia alters fetal endothelial gene expression and disturbs cytokines- and growth factors-induced endothelial responses. RNA sequencing analysis was performed on unpassaged human umbilical vein endothelial cells (HUVECs) from normotensive and preeclamptic pregnancies. Functional assays for endothelial monolayer integrity, proliferation, and migration were conducted on passage 1 HUVECs from normotensive and preeclamptic pregnancies. Compared with normotensive cells, 926 and 172 genes were dysregulated in unpassaged female and male HUVECs from preeclamptic pregnancies, respectively. Many of these preeclampsia-dysregulated genes are associated with cardiovascular diseases (eg, heart failure) and endothelial function (eg, cell migration, calcium signaling, and endothelial nitric oxide synthase signaling). TNF (tumor necrosis factor)-α-, TGF (transforming growth factor)-β1-, FGF (fibroblast growth factor)-2-, and VEGFA (vascular endothelial growth factor A)-regulated gene networks were differentially disrupted in unpassaged female and male HUVECs from preeclamptic pregnancies. Moreover, preeclampsia decreased endothelial monolayer integrity in responses to TNF-α in both female and male HUVECs. Preeclampsia decreased TGF-β1-strengthened monolayer integrity in female HUVECs, whereas it enhanced FGF-2-strengthened monolayer integrity in male HUVECs. Preeclampsia promoted TNF-α-, TGF-β1-, and VEGFA-induced cell proliferation in female, but not in male HUVECs. Preeclampsia inhibited TNF-α-induced cell migration in female HUVECs, but had an opposite effect on male HUVECs. In conclusion, preeclampsia differentially dysregulates cardiovascular diseases- and endothelial function-associated genes/pathways in female and male fetal endothelial cells in association with the sexual dimorphisms of preeclampsia-dysregulated fetal endothelial function.

Project description:BackgroundSeed germination involves progression from complete metabolic dormancy to a highly active, growing seedling. Many factors regulate germination and these interact extensively, forming a complex network of inputs that control the seed-to-seedling transition. Our understanding of the direct regulation of gene expression and the dynamic changes in the epigenome and small RNAs during germination is limited. The interactions between genome, transcriptome and epigenome must be revealed in order to identify the regulatory mechanisms that control seed germination.ResultsWe present an integrated analysis of high-resolution RNA sequencing, small RNA sequencing and MethylC sequencing over ten developmental time points in Arabidopsis thaliana seeds, finding extensive transcriptomic and epigenomic transformations associated with seed germination. We identify previously unannotated loci from which messenger RNAs are expressed transiently during germination and find widespread alternative splicing and divergent isoform abundance of genes involved in RNA processing and splicing. We generate the first dynamic transcription factor network model of germination, identifying known and novel regulatory factors. Expression of both microRNA and short interfering RNA loci changes significantly during germination, particularly between the seed and the post-germinative seedling. These are associated with changes in gene expression and large-scale demethylation observed towards the end of germination, as the epigenome transitions from an embryo-like to a vegetative seedling state.ConclusionsThis study reveals the complex dynamics and interactions of the transcriptome and epigenome during seed germination, including the extensive remodelling of the seed DNA methylome from an embryo-like to vegetative-like state during the seed-to-seedling transition. Data are available for exploration in a user-friendly browser at https://jbrowse.latrobe.edu.au/germination_epigenome .

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Transcriptomic Remodelling of Fetal Endothelial Cells During Establishment of Inflammatory Memory.

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