Forced expression of the non-coding RNA miR-17∼92 restores activation and function in CD28-deficient CD4+ T cells

Dölz, Marianne; Hasiuk, Marko; Gagnon, John D.; Kornete, Mara; Marone, Romina; Bantug, Glenn R.; Kageyama, Robin; Hess, Christoph; Ansel, K. Mark; Seyres, Denis; Roux, Julien; Jeker, Lukas T.

doi:10.1016/j.isci.2022.105372

Cited by 7 publications

(14 citation statements)

References 83 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although the experimental setups were not identical -Hsin and colleagues did not sort 48h activated cells according to cell divisions and the poly(A)-seq protocol they used differs slightly from the A-seq2 protocol -the covered genes and genomic distribution was comparable (Hsin et al, 2018) (Figure S1E). Similar important activation effects, when comparing naïve to 48h activated cells, have also been observed by analysing the transcriptome (Dölz et al, 2022). Finally, we observed an equivalent distribution of the variance when re-analysing the poly(A)-seq data generated by Hsin and colleagues (Figure S1F).…”

Section: Resultssupporting

confidence: 82%

“…While many recent studies have focused on the mechanisms regulating the choice of poly(A) sites (Bucheli et al, 2007;Larochelle, Hunyadkürti and Bachand, 2017;Gruber et al, 2018;Grassi et al, 2019), decoupling transcriptional and post-transcriptional effects in the regulation of isoform abundance remains a key challenge. We interrogated our dataset by comparing it to a previously generated orthogonal total mRNA sequencing dataset generated from naïve and 48h activated CD4 + T cells (Dölz et al, 2022). While the activation period of this dataset matched with our study, it did not discriminate cells by division.…”

Section: Apa Events and Transcript Abundance Regulationmentioning

confidence: 78%

“…5/218 miRNA binding sites were significantly enriched relative to background (Fisher's exact test; p value < 0.05; background was genes expressed in CD4+ T cells) in shortened genes only (Figure 4F). Among the miRNAs expressed in T cells, we found enrichment for miR-18-5p which is part of the miR-17-92 cluster and known to be involved in T cell activation and differentiation (Dölz et al, 2022) and miR-103-3p/107-3p and miR-500-3p/501-3p which are not characterised in T cells yet. Present analysis suggested a well-balanced system in which APA usage has limited effect on global gene expression.…”

Section: Apa Events and Transcript Abundance Regulationmentioning

confidence: 86%

“…PacBio long-read sequencing data are accessible under accession ID GSE209604. mRNAseq dataset (Dölz et al, 2022) are available under accession ID GSE140568 and miRNAseq dataset will be available in the future under accession ID GSE203633. Code is available at https://gitlab.com/JekerLab/dynamic-3p-utr-changes-in-cd4-t-cell.…”

Section: Data and Code Availabilitymentioning

confidence: 99%

See 3 more Smart Citations

T helper cells exhibit a dynamic and reversible 3’UTR landscape

Seyres

Gorka

Schmidt

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

3' untranslated regions (3'UTRs) are critical elements of messenger RNAs, as they contain binding sites for RNA-binding proteins (RBP) and microRNAs that affect various aspects of the RNA life cycle including transcript stability and cellular localisation. In response to T cell receptor activation, T cells undergo massive expansion during the effector phase of the immune response and dynamically modify their 3'UTRs. Whether this serves to directly regulate the abundance of specific mRNAs or is a secondary effect of proliferation remains unclear. To study 3'UTR dynamics in T helper cells we investigated division-dependent alternative polyadenylation (APA). We generated 3' end UTR sequencing data from naive, activated, memory and regulatory CD4+ T cells. 3'UTR length changes were estimated using a non-negative matrix factorization approach and were compared with those inferred from long-read PacBio sequencing. We found that APA events were transient and reverted after effector phase expansion. Using an orthogonal bulk RNAseq dataset, we did not find evidence of APA association with differential gene expression or transcript usage, indicating that APA has only a marginal effect on transcript abundance. 3'UTR sequence analysis revealed conserved binding sites for T cell-relevant microRNAs and RBPs in the alternative 3'UTRs. These results indicate that polyA site usage could play an important role in the control of cell fate decisions and homeostasis.

show abstract

Section: Resultssupporting

confidence: 82%

Section: Apa Events and Transcript Abundance Regulationmentioning

confidence: 78%

Section: Apa Events and Transcript Abundance Regulationmentioning

confidence: 86%

Section: Data and Code Availabilitymentioning

confidence: 99%

See 2 more Smart Citations

T helper cells exhibit a dynamic and reversible 3’UTR landscape

Seyres

Gorka

Schmidt

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…36 Most recently, miR-17-92 was reported to rescue CD28 deficiency and by this restore T cell activation and function. 37 Furthermore, miRNAs of the miR-17-92 family are critical regulators of the differentiation of TFH (follicular T helper) cells and thus the generation of appropriate germinal center B cell responses. 38,39 They also regulate effector and memory CD8+ T-cell fates and enhance their cytotoxic activity.…”

Section: Discussionmentioning

confidence: 99%

Identification of extracellular vesicle microRNA signatures specifically linked to inflammatory and metabolic mechanisms in obesity‐associated low type‐2 asthma

Alhamdan

Greulich

Daviaud

et al. 2023

Allergy

View full text Add to dashboard Cite

Rationale and ObjectivePlasma extracellular vesicles (EVs) represent a vital source of molecular information about health and disease states. Due to their heterogenous cellular sources, EVs and their cargo may predict specific pathomechanisms behind disease phenotypes. Here we aimed to utilize EV microRNA (miRNA) signatures to gain new insights into underlying molecular mechanisms of obesity‐associated low type‐2 asthma.MethodsObese low type‐2 asthma (OA) and non‐obese low type‐2 asthma (NOA) patients were selected from an asthma cohort conjointly with healthy controls. Plasma EVs were isolated and characterised by nanoparticle tracking analysis. EV‐associated small RNAs were extracted, sequenced and bioinformatically analysed.ResultsBased on EV miRNA expression profiles, a clear distinction between the three study groups could be established using a principal component analysis. Integrative pathway analysis of potential target genes of the differentially expressed miRNAs revealed inflammatory cytokines (e.g., interleukin‐6, transforming growth factor‐beta, interferons) and metabolic factors (e.g., insulin, leptin) signalling pathways to be specifically associated with OA. The miR‐17–92 and miR‐106a–363 clusters were significantly enriched only in OA. These miRNA clusters exhibited discrete bivariate correlations with several key laboratory (e.g., C‐reactive protein) and lung function parameters. Plasma EV miRNA signatures mirrored blood‐derived CD4+ T‐cell transcriptome data, but achieved an even higher sensitivity in identifying specifically affected biological pathways.ConclusionThe identified plasma EV miRNA signatures and particularly the miR‐17–92 and ‐106a–363 clusters were capable to disentangle specific mechanisms of the obesity‐associated low type‐2 asthma phenotype, which may serve as basis for stratified treatment development.

show abstract