Gene activation precedes DNA demethylation in response to infection in human dendritic cells

Pacis, Alain; Mailhot-Léonard, Florence; Tailleux, Ludovic; Randolph, Haley E.; Yotova, Vania; Dumaine, Anne; Grenier, Jean; Barreiro, Luis B.

doi:10.1073/pnas.1814700116

Cited by 126 publications

(98 citation statements)

References 57 publications

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“…From the co-expression and co-methylation network perspective, it is still challenging to interpret as the DNA methylation play a very important role in regulating the gene expression. A recent study might support our finding, which suggested that DNA methylation would rather play a role in fine tuning gene expression regulation (64). And then by applying RegEnrich, we predicted a key regulator network which potentially play important roles in CXCL4-moDCs phenotyping.…”

Section: Discussionsupporting

confidence: 80%

CXCL4 Links Inflammation and Fibrosis by Reprogramming Monocyte-Derived Dendritic Cells in vitro

et al. 2020

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Fibrosis is a condition shared by numerous inflammatory diseases. Our incomplete understanding of the molecular mechanisms underlying fibrosis has severely hampered effective drug development. CXCL4 is associated with the onset and extent of fibrosis development in multiple inflammatory and fibrotic diseases. Here, we used monocyte-derived cells as a model system to study the effects of CXCL4 exposure on dendritic cell development by integrating 65 longitudinal and paired whole genome transcriptional and methylation profiles. Using data-driven gene regulatory network analyses, we demonstrate that CXCL4 dramatically alters the trajectory of monocyte differentiation, inducing a novel pro-inflammatory and pro-fibrotic phenotype mediated via key transcriptional regulators including CIITA. Importantly, these pro-inflammatory cells directly trigger a fibrotic cascade by producing extracellular matrix molecules and inducing myofibroblast differentiation. Inhibition of CIITA mimicked CXCL4 in inducing a pro-inflammatory and pro-fibrotic phenotype, validating the relevance of the gene regulatory network. Our study unveils that CXCL4 acts as a key secreted factor driving innate immune training and forming the long-sought link between inflammation and fibrosis.

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Section: Discussionsupporting

confidence: 80%

CXCL4 Links Inflammation and Fibrosis by Reprogramming Monocyte-Derived Dendritic Cells in vitro

et al. 2020

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“…Thus, DNA methylation and differential expression did not correlate over time despite evidence of their association revealed by CpGOE values. DNA methylation and differential expression do not necessarily correlate throughout time when a causal relationship is present (Secco et al, 2015;Pacis et al, 2019), and have been documented to be unpaired during invertebrate development under high pCO 2 (Strader et al, in review). The relationship between DNA methylation and gene expression in molluscs has proved tenuous in some cases.…”

Section: Evidence Of a Role For Dna Methylation In Differential Exprementioning

confidence: 99%

Changes in Genome-Wide Methylation and Gene Expression in Response to Future pCO2 Extremes in the Antarctic Pteropod Limacina helicina antarctica

2020

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Epigenetic processes such as variation in DNA methylation may promote phenotypic plasticity and the rapid acclimatization of species to environmental change. The extent to which an organism can mount an epigenetic response to current and future climate extremes may influence its capacity to acclimatize or adapt to global change on ecological rather than evolutionary time scales. The thecosome pteropod Limacina helicina antarctica is an abundant macrozooplankton endemic to the Southern Ocean and is considered a bellwether of ocean acidification as it is highly sensitive to variation in carbonate chemistry. In this study, we quantified variation in DNA methylation and gene expression over time across different ocean acidification regimes. We exposed L. helicina antarctica to pCO 2 levels mimicking present-day norms in the coastal Southern Ocean of 255 µatm pCO 2 , present-day extremes of 530 µatm pCO 2 , and projected extremes of 918 µatm pCO 2 for up to 7 days before measuring global DNA methylation and sequencing transcriptomes in animals from each treatment across time. L. helicina antarctica significantly reduced DNA methylation by 29-56% after 1 day of exposure to 918 µatm pCO 2 before DNA methylation returned to control levels after 6 days. In addition, L. helicina antarctica exposed to 918 µatm pCO 2 exhibited drastically more differential expression compared to cultures replicating present-day pCO 2 extremes. Differentially expressed transcripts were predominantly downregulated. Furthermore, downregulated genes were enriched with signatures of gene body methylation. These findings support the potential role of DNA methylation in regulating transcriptomic responses by L. helicina antarctica to future ocean acidification and in situ variation in pCO 2 experienced seasonally or during vertical migration. More broadly, L. helicina antarctica was capable of mounting a substantial epigenetic response to ocean acidification despite little evidence of metabolic compensation or recovery of the cellular stress response in this species at future pCO 2 levels.

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“…Whereas the classical dogma is that gene methylation regulates gene expression, recent studies evidenced that DNA methylation changes may happen after changes in gene expression. Pacis et al identified lower DNA methylation level in dendritic cells post Mycobacterium tuberculosis infection, but the detectable losses in methylation occurred after the changes in gene expression, indicating the demethylation was a downstream consequence of transcriptional activation [107]. The results also suggested that DNA demethylation in response to infection could play a role in facilitating the binding of methylation-sensitive transcription factors (TFs) at enhancers and may relate to innate immune memory.…”

Section: Relationships Between Epigenetic Regulation and Gene Expressionmentioning

confidence: 99%

The role of epigenetics in the development of childhood asthma

Koppelman

2019

Expert Review of Clinical Immunology

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Introduction: The development of childhood asthma is caused by a combination of genetic factors and environmental exposures. Epigenetics describes mechanisms of (heritable) regulation of gene expression that occur without changes in DNA sequence. Epigenetics is strongly related to aging, is cell-type specific, and includes DNA methylation, noncoding RNAs, and histone modifications. Areas covered: This review summarizes recent epigenetic studies of childhood asthma in humans, which mostly involve studies of DNA methylation published in the recent five years. Environmental exposures, in particular cigarette smoking, have significant impact on epigenetic changes, but few of these epigenetic signals are also associated with asthma. Several asthma-associated genetic variants relate to DNA methylation. Epigenetic signals can be better understood by studying their correlation with gene expression, which revealed higher presence and activation of blood eosinophils in asthma. Strong associations of nasal methylation signatures and atopic asthma were identified, which were replicable across different populations. Expert commentary: Epigenetic markers have been strongly associated with asthma, and might serve as biomarker of asthma. The causal and longitudinal relationships between epigenetics and disease, and between environmental exposures and epigenetic changes need to be further investigated. Efforts should be made to understand cell-type-specific epigenetic mechanisms in asthma.

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Gene activation precedes DNA demethylation in response to infection in human dendritic cells

Cited by 126 publications

References 57 publications

CXCL4 Links Inflammation and Fibrosis by Reprogramming Monocyte-Derived Dendritic Cells in vitro

CXCL4 Links Inflammation and Fibrosis by Reprogramming Monocyte-Derived Dendritic Cells in vitro

Changes in Genome-Wide Methylation and Gene Expression in Response to Future pCO2 Extremes in the Antarctic Pteropod Limacina helicina antarctica

The role of epigenetics in the development of childhood asthma

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