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Analysis of HERV transcriptome in PBMCs upon dose dependent LPS stimulations identifies HERVs and genes shared signaling pathways

ABSTRACT: Analysis of HERV transcriptome in PBMCs upon dose dependent LPS stimulations identifies HERVs and genes shared signaling pathways

PROVIDER: PRJNA422901 | ENA |

REPOSITORIES: ENA

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Analysis of HERV transcriptome in PBMCs upon dose dependent LPS stimulations identifies HERVs and genes shared signaling pathways

Project description:Human endogenous retroviruses (HERVs/MaLRs) are distributed among our 24 chromosomes and their long terminal repeats (LTRs) constitute putative regulatory sequences. HERVs have received much attention for their implication in cancer, autoimmunity and placental development. Herein, we used a recently described high-density microarray allowing the exploration of the whole HERVs/MaLRs transcriptome including 353,994 HERVs/MaLRs loci and also 1559 genes related to immunity. We obtained a first view of the HERV transcriptome in peripheral blood mononuclear cells (PBMCs) by using a composite panel of unstimulated, low dose and high dose LPS-stimulated PBMCs from healthy volunteers to mimic inflammatory response or monocyte anergy. About 5.6% of the HERVs/MaLRs repertoire is transcribed in PBMCs. Roughly, one tenth [5.7%-13.1%] of LTRs present a constitutive promoter or polyA function and a quarter [19.5%-27.6%] of LTRs may shift from silent to active LTRs, LTRs being broadly subjected to operational determinism. We provide evidence that some HERVs/MaLRs and genes share similar control of regulation upon LPS stimulation conditions, e.g. presenting a low dose LPS-dependent “tolerizable” profile which can be reversed by INF-g stimulation. Similarly to tissue tropism observed in solid tumors, stimulus-dependent response confirm that the expression of HERVs is tightly regulated in PBMCs. Altogether, these observations allow to integrate 62 HERVs/MaLRs and 26 genes in 11 canonical pathways. We highlight HERVs close to OAS2/3 and IFI44/IFI44L genes. HERV incorporation at the crossroads of immune response pathways, paves the way for further functional studies and analyses of HERV transcriptome in altered immune responses in vivo such as in sepsis.

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Project description:The endogenous retrovirus type W (HERV-W) is a human specific entity, which was initially discovered in multiple sclerosis (MS) patient derived cells. We initially found that the HERV-W envelope (ENV) protein negatively affects oligodendrogenesis and controls microglial cell polarization towards a myelinated axon associated and damaging phenotype. Such first functional assessments were conducted ex vivo, given the human specific origin of HERV-W. Recent experimental evidence gathered on a novel transgenic mouse model, mimicking activation and expression of the HERV-W ENV protein, revealed that all glial cell types are impacted and that cellular fates, differentiation, and functions were changed. In order to identify a HERV-W specific signature in glial cells, the current study analyzed the transcriptome of ENV stimulated microglial- and astroglial cells and compared the transcriptomic signature to lipopolysaccharide (LPS) stimulated cells, owing to the fact that both ligands can activate toll-like receptor-4 (TLR-4). Additionally, a comparison between published disease associated glial signatures and the transcriptome of HERV-W ENV stimulated glial cells was conducted. We, therefore, provide here for the first time a detailed molecular description of specific HERV-W ENV evoked effects on those glial cell populations that are involved in smoldering neuroinflammatory processes relevant for progression of neurodegenerative diseases.

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