Promoter H3K4 methylation dynamically reinforces activation-induced pathways in human CD4 T cells

LaMere, Sarah A.; Thompson, Ryan; Komori, H. Kiyomi; Mark, Adam; Salomon, Daniel R.

doi:10.1038/gene.2016.19

Cited by 27 publications

(30 citation statements)

References 58 publications

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“…This chromatin remodelling correlates with changes in the expression of genes that are pivotal for the innate immune response to mycobacteria (Alcaraz-Lopez et al, 2017; Malone et al, 2018; Nalpas et al, 2015). Our work supports the hypothesis that chromatin modifications of the host macrophage genome play an essential role during intracellular infections by mycobacterial pathogens (Cheng et al, 2014; LaMere et al, 2016).…”

Section: Discussionsupporting

confidence: 88%

Alveolar macrophage chromatin is modified to orchestrate host response toMycobacterium bovisinfection

Hall

Vernimmen

Browne

et al. 2019

Preprint

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BackgroundBovine tuberculosis is caused by infection withMycobacterium bovis, which can also cause disease in a range of other mammals, including humans. Alveolar macrophages are the key immune effector cells that first encounterM. bovisand how the macrophage epigenome responds to mycobacterial pathogens is currently not well understood.ResultsHere, we have used chromatin immunoprecipitation sequencing (ChIP-seq), RNA-seq and miRNA-seq to examine the effect ofM. bovisinfection on the bovine alveolar macrophage (bAM) epigenome. We show that H3K4me3 is more prevalent, at a genome-wide level, in chromatin fromM. bovis-infected bAM compared to control non-infected bAM; this was particularly evident at the transcriptional start sites of genes that determine programmed macrophage responses to mycobacterial infection (e.g. M1/M2 macrophage polarisation). This pattern was also supported by the distribution of RNA Polymerase II (PolII) ChIP-seq results, which highlighted significantly increased transcriptional activity at genes demarcated by permissive chromatin. Identification of these genes enabled integration of high-density GWAS data, which revealed genomic regions associated with resilience to infection withM. bovisin cattle.ConclusionsThrough integration of these data, we show that bAM transcriptional reprogramming occurs through differential distribution of H3K4me3 and PolII at key immune genes. Furthermore, this subset of genes can be used to prioritise genomic variants from a relevant GWAS data set.

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Section: Discussionsupporting

confidence: 88%

Alveolar macrophage chromatin is modified to orchestrate host response toMycobacterium bovisinfection

Hall

Vernimmen

Browne

et al. 2019

Preprint

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“…We analyzed RNA expression to compare genes with H3K4me3 peaks from our previous data set (25) versus H3K27me3 and confirmed that genes from all conditions containing H3K27me3 promoter peaks had significantly lower RNA expression (Supplementary Figure S2F and Supplementary Table S1). Therefore, as previously described (6), genes with H3K27me3 peaks are associated with suppression of RNA expression, and this association is maintained throughout T cell activation in naïve and memory CD4 subsets.…”

Section: Resultssupporting

confidence: 62%

“…We find that in both subsets, profound demethylation of H3K27 is observed by 1 day after activation, which is in contrast to H3K4 methylation, where changes are not observed until days later (25). Mapping specific states of H3K27me3 to known immune pathways demonstrates that loss of H3K27me3 early in activation corresponds to pathways crucial to T cell function, including T cell activation and the JAK-STAT pathways.…”

Section: Introductionmentioning

confidence: 58%

“…Based on our previous data, histone modifications are dynamic during CD4 T cell activation in both naïve and memory CD4 T cells (25), and this is the first kinetic study of post-activation H3K27me3 marks comparing naïve vs. memory CD4 T cells. We previously showed enrichment for H3K4me2 and H3K4me3 changes in both directions but only relatively late (i.e.…”

Section: Resultsmentioning

confidence: 93%

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H3K27 Methylation Dynamics during CD4 T Cell Activation: Regulation of JAK/STAT and IL12RB2 Expression by JMJD3

LaMere

Thompson

Meng

et al. 2017

The Journal of Immunology

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The changes to the epigenetic landscape in response to antigen during CD4 T cell activation have not been well characterized. While CD4 T cell subsets have been mapped globally for numerous epigenetic marks, little has been done to study their dynamics early after activation. We have studied changes to promoter H3K27me3 during activation of human naïve and memory CD4 T cells. Our results show that these changes occur relatively early (1 day) after activation of both naïve and memory cells, and that demethylation is the predominant change to H3K27me3 at this time point, reinforcing high expression of target genes. Additionally, inhibition of the H3K27 demethylase, JMJD3, in naïve CD4 T cells demonstrates how critically important molecules required for T cell differentiation, such as JAK2 and IL12RB2, are regulated by H3K27me3. Our results demonstrate that H3K27me3 is a dynamic and important epigenetic modification during CD4 T cell activation, and that JMJD3-driven H3K27 demethylation is critical for CD4 T cell function.

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“…Next, we asked if human naïve and memory CD4 + T cells can express FURIN upon receiving TCR signals. We addressed this question using the time course RNA-seq analysis of CD45RA + CD45RO − CD4 + naïve T-cells and CD45RA − CD45RO + CD4 + memory T-cells which were obtained from 4 individuals and activated by anti-CD3 and anti-CD28 antibodies 36 .…”

Section: Furin Is Induced In Activated Cd4 + T-cells Upon Tcr Signalsmentioning

confidence: 99%

T-cell hyperactivation and paralysis in severe COVID-19 infection revealed by single-cell analysis

Kalfaoglu

Almeida‐Santos

Tye

et al. 2020

Preprint

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Severe COVID-19 patients can show respiratory failure, T-cell reduction, and cytokine release syndrome (CRS), which can be fatal in both young and aged patients and is a major concern of the pandemic. However, the pathogenetic mechanisms of CRS in COVID-19 are poorly understood. Here we show single cell-level mechanisms for T-cell dysregulation in severe SARS-CoV-2 infection, and thereby demonstrate the mechanisms underlying T-cell hyperactivation and paralysis in severe COVID-19 patients. By in silico sorting CD4+ T-cells from a single cell RNA-seq dataset, we found that CD4+ T-cells were highly activated and showed unique differentiation pathways in the lung of severe COVID-19 patients. Notably, those T-cells in severe COVID-19 patients highly expressed immunoregulatory receptors and CD25, whilst repressing the expression of the transcription factor FOXP3 and interestingly, both the differentiation of regulatory T-cells (Tregs) and Th17 was inhibited. Meanwhile, highly activated CD4 + T-cells express PD-1 alongside macrophages that express PD-1 ligands in severe patients, suggesting that PD-1-mediated immunoregulation was partially operating. Furthermore, we show that CD25 + hyperactivated T-cells differentiate into multiple helper T-cell lineages, showing multifaceted effector T-cells with Th1 and Th2 characteristics. Lastly, we show that CD4 + T-cells, particularly CD25-expressing hyperactivated T-cells, produce the protease Furin, which facilitates the viral entry of SARS-CoV-2. Collectively, CD4 + T-cells from severe COVID-19 patients are hyperactivated and FOXP3-mediated negative feedback mechanisms are impaired in the lung, while activated CD4 + T-cells continue to promote further viral infection through the production of Furin.Therefore, our study proposes a new model of T-cell hyperactivation and paralysis that drives pulmonary damage, systemic CRS and organ failure in severe COVID-19 patients.

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Promoter H3K4 methylation dynamically reinforces activation-induced pathways in human CD4 T cells

Cited by 27 publications

References 58 publications

Alveolar macrophage chromatin is modified to orchestrate host response toMycobacterium bovisinfection

Alveolar macrophage chromatin is modified to orchestrate host response toMycobacterium bovisinfection

H3K27 Methylation Dynamics during CD4 T Cell Activation: Regulation of JAK/STAT and IL12RB2 Expression by JMJD3

T-cell hyperactivation and paralysis in severe COVID-19 infection revealed by single-cell analysis

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