scholarly journals A DNA methylome biosignature in alveolar macrophages from TB-exposed individuals predicts exposure to mycobacteria

2021 ◽  
Author(s):  
Maria Lerm ◽  
Jyotirmoy Das ◽  
Jakob Paues ◽  
Nina Idh ◽  
Isabelle Pehrson
Keyword(s):  
Dna Methylation ◽  
Immune Cells ◽  
Contact Tracing ◽  
Clinical Use ◽  
Strongly Correlated ◽  
Epigenetic Changes ◽  
Dna Methylome ◽  
Hla Dr ◽  
Lung Compartment ◽  
Unsupervised Cluster Analysis

Several studies have identified biomarkers for tuberculosis (TB) diagnosis based on blood cell transcriptomics. Here, we instead studied epigenomics in the lung compartment by obtaining induced sputum from subjects included in a TB contact tracing. CD3- and HLA-DR-positive cells were isolated from the collected sputum and DNA methylome analyses performed. Unsupervised cluster analysis revealed that DNA methylomes of cells from TB-exposed individuals and controls appeared as separate clusters and the numerous genes that were differentially methylated were functionally connected. The enriched pathways were strongly correlated to data from published work on protective heterologous immunity to TB. Taken together, our results demonstrate that epigenetic changes related to trained immunity occurs in the pulmonary immune cells of TB-exposed individuals and that a DNA methylation signature can be derived from the DNA methylome. Such a signature can be further developed for clinical use as a marker of TB exposure.

scholarly journals DNA Methylation Profiles of Immune Cells From Tuberculosis-Exposed Individuals Overlap With BCG-Induced Epigenetic Changes

2022 ◽  
Author(s):  
Isabelle Pehrson ◽  
Nina Idh ◽  
Clara Braian ◽  
Jakob Paues ◽  
Jyotirmoy Das ◽  
...  
Keyword(s):  
Immune Cells ◽  
Animal Studies ◽  
Contact Tracing ◽  
Strongly Correlated ◽  
Epigenetic Changes ◽  
Trained Immunity ◽  
Hla Dr ◽  
Lung Compartment ◽  
Unsupervised Cluster Analysis

Abstract The mechanism of protection of the only approved tuberculosis (TB) vaccine, Bacillus Calmette Guérin (BCG) is poorly understood. In recent years, epigenetic modifications induced by BCG have been demonstrated to reflect a state of trained immunity. The concept of trained immunity is now explored as a potential prevention strategy for a variety of infections. Studies on human TB immunity are dominated by those using peripheral blood as surrogate markers for immunity. Here, we instead studied the lung compartment by obtaining induced sputum from subjects included in a TB contact tracing. CD3- and HLA-DR-positive cells were isolated from the collected sputum and DNA methylome analyses performed. Unsupervised cluster analysis revealed that DNA methylomes of cells from TB-exposed individuals and controls appeared as separate clusters, and the numerous genes that were differentially methylated were functionally connected. The enriched pathways were strongly correlated to previously reported epigenetic changes and trained immunity in immune cells exposed to the BCG vaccine in human and animal studies. We further demonstrated that similar pathways were epigenetically modified in human macrophages trained with BCG in vitro. Altogether, our study demonstrates that similar epigenetic changes are induced by M. tuberculosis and BCG.

scholarly journals DNA methylation profiling of immune cells from tuberculosis-exposed individuals overlaps with BCG-induced epigenetic changes and correlates with the emergence of anti-mycobacterial ‘corralling cells’

2021 ◽  
Author(s):  
Isabelle Pehrson ◽  
Clara Braian ◽  
Lovisa Karlsson ◽  
Nina Idh ◽  
Eva Kristin Danielsson ◽  
...  
Keyword(s):  
Immune Cells ◽  
Animal Studies ◽  
Defense Mechanism ◽  
Contact Tracing ◽  
Strongly Correlated ◽  
Epigenetic Changes ◽  
Trained Immunity ◽  
Hla Dr ◽  
Lung Compartment

AbstractThe mechanism of protection of the only approved tuberculosis (TB) vaccine, Bacillus Calmette Guérin (BCG) is poorly understood. In recent years, epigenetic modifications induced by BCG have been demonstrated to reflect a state of trained immunity. The concept of trained immunity is now explored as a potential prevention strategy for a variety of infections. Studies on human TB immunity are dominated by those using peripheral blood as surrogate markers for immunity. Here, we instead studied the lung compartment by obtaining induced sputum from subjects included in a TB contact tracing. CD3- and HLA-DR-positive cells were isolated from the collected sputum and DNA methylome analyses performed. Unsupervised cluster analysis revealed that DNA methylomes of cells from TB-exposed individuals and controls appeared as separate clusters, and the numerous genes that were differentially methylated were functionally connected. The enriched pathways were strongly correlated to previously reported epigenetic changes and trained immunity in immune cells exposed to the BCG vaccine in human and animal studies. We further demonstrated that similar pathways were epigenetically modified in human macrophages trained with BCG in vitro. Finally, we found evidence of an M. tuberculosis-triggered emergence of a non-macrophage cell population from BCG-trained macrophage cultures. These cells did not phagocytose M. tuberculosis, but ‘corralled’ the bacteria into focal points, resulting in limitation of bacterial growth. Altogether, our study demonstrates that similar epigenetic changes are induced by M. tuberculosis and BCG and suggests that the modifications promote transformation of macrophages (or an unknown progenitor) to establish a yet undescribed cellular defense mechanism which we term ‘corralling’, based on the metaphorical resemblance to sheepdog herding.

scholarly journals LAG3(LAG-3,CD223) DNA methylation correlates with LAG3 expression by tumor and immune cells, immune cell infiltration, and overall survival in clear cell renal cell carcinoma

2020 ◽  
Vol 8 (1) ◽  
pp. e000552 ◽  
Author(s):  
Niklas Klümper ◽  
Damian J Ralser ◽  
Emma Grace Bawden ◽  
Jenny Landsberg ◽  
Romina Zarbl ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Overall Survival ◽  
Cell Lines ◽  
Immune Cells ◽  
Immune Cell ◽  
Clear Cell ◽  
Immune Cell Infiltration ◽  
Strongly Correlated ◽  
Cell Renal Cell Carcinoma ◽  
Immune Cell Infiltrates

BackgroundLymphocyte activating 3 (LAG3, LAG-3, CD223) is a promising target for immune checkpoint inhibition in clear cell renal cell carcinoma (KIRC). The aim of this study was to investigate the epigenetic regulation ofLAG3in KIRC by methylation.MethodsWe correlated quantitativeLAG3methylation levels with transcriptional activity, immune cell infiltration, and overall survival in a cohort of n=533 patients with KIRC and n=160 normal adjacent tissue (NAT) samples obtained from The Cancer Genome Atlas (TCGA). Furthermore, we analyzedLAG3methylation in peripheral blood mononuclear cells (PBMCs) and KIRC cell lines. We validated correlations between LAG3 expression, immune cell infiltrates, survival, and methylation in an independent KIRC cohort (University Hospital Bonn (UHB) cohort, n=118) by means of immunohistochemistry and quantitative methylation-specific PCR.ResultsWe found differential methylation profiles among PBMCs, NAT, KIRC cell lines, and KIRC tumor tissue. Methylation strongly correlated with LAG3 mRNA expression in KIRCs (TCGA cohort) and KIRC cell lines. In the UHB cohort, methylation correlated with LAG3-positive immune cells and tumor-intrinsic LAG3 protein expression. Furthermore,LAG3methylation strongly correlated with signatures of distinct immune cell infiltrates, an interferon-y signature (TCGA cohort), and immunohistochemically quantified CD45+, CD8+, and CD4+immune cell infiltrates (UHB cohort). LAG3 mRNA expression (TCGA cohort), methylation (both cohorts), and tumor cell-intrinsic protein expression (UHB cohort) was significantly associated with overall survival.ConclusionOur data suggest an epigenetic regulation of LAG3 expression in tumor and immune cells via DNA methylation. LAG3 expression and methylation is associated with a subset of KIRCs showing a distinct clinical course and immunogenicity. Our study provides rationale for further testingLAG3DNA methylation as a predictive biomarker for response to LAG3 immune checkpoint inhibitors.

scholarly journals A differential DNA methylome signature of pulmonary immune cells from individuals converting to latent tuberculosis infection

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lovisa Karlsson ◽  
Jyotirmoy Das ◽  
Moa Nilsson ◽  
Amanda Tyrén ◽  
Isabelle Pehrson ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Immune Cells ◽  
Methylation Status ◽  
Latent Tuberculosis ◽  
Metabolic Reprogramming ◽  
Dna Methylome ◽  
Differentially Methylated Genes ◽  
Increased Risk ◽  
Latent Tb ◽  
Latent Tb Infection

AbstractTuberculosis (TB), caused by Mycobacterium tuberculosis, spreads via aerosols and the first encounter with the immune system is with the pulmonary-resident immune cells. The role of epigenetic regulations in the immune cells is emerging and we have previously shown that macrophages capacity to kill M. tuberculosis is reflected in the DNA methylome. The aim of this study was to investigate epigenetic modifications in alveolar macrophages and T cells in a cohort of medical students with an increased risk of TB exposure, longitudinally. DNA methylome analysis revealed that a unique DNA methylation profile was present in healthy subjects who later developed latent TB during the study. The profile was reflected in a different overall DNA methylation distribution as well as a distinct set of differentially methylated genes (DMGs). The DMGs were over-represented in pathways related to metabolic reprogramming of macrophages and T cell migration and IFN-γ production, pathways previously reported important in TB control. In conclusion, we identified a unique DNA methylation signature in individuals, with no peripheral immune response to M. tuberculosis antigen who later developed latent TB. Together the study suggests that the DNA methylation status of pulmonary immune cells can reveal who will develop latent TB infection.

scholarly journals A Differential DNA Methylome Signature of Pulmonary Immune Cells from Individuals Converting to Latent Tuberculosis Infection

2021 ◽  
Author(s):  
Lovisa Karlsson ◽  
Jyotirmoy Das ◽  
Moa Nilsson ◽  
Amanda Tyren ◽  
Isabelle Pehrson ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Immune Cells ◽  
Methylation Status ◽  
Latent Tuberculosis ◽  
Dna Methylome ◽  
T Cell Migration ◽  
Increased Risk ◽  
Before And After ◽  
Methylome Analysis ◽  
Latent Tb

Tuberculosis (TB), caused by Mycobacterium tuberculosis, spreads via aerosols and the first encounter with the immune system is with the pulmonary resident immune cells. The role of epigenetic regulations through DNA methylation in the immune cells is emerging. We have previously shown that capacity to kill M. tuberculosis is reflected in the DNA methylome. The aim of this study was to investigate epigenetic modifications in the pulmonary immune cells in a cohort of medical students with a previously documented increased risk of TB exposure, longitudinally. Sputum samples containing alveolar macrophages (AMs) and T cells were collected before and after study subjects worked in hospital departments with a high-risk of TB exposure. DNA methylome analysis revealed that a unique DNA methylation profile was present already at inclusion in subjects who developed latent TB during the study. The profile was both reflected in different overall DNA methylation distribution as well as more profound alterations in the methylation status of a unique set of CpG-sites. Over-representation analysis of the DMGs showed enrichment in pathways related to metabolic reprograming of macrophages and T cell migration and IFN-γ production. In conclusion, we identified a unique DNA methylation signature in individuals, while still IGRA-negative and who later developed latent TB. Epigenetic regulation was found in pathways that have previously been reported to be important in TB. Together the study suggests that DNA methylation status of pulmonary immune cells can predict IGRA conversion.

Epigenetics, Nutrition, Disease and Drug Development

2019 ◽  
Vol 16 (4) ◽  
pp. 386-391 ◽  
Author(s):  
Kenneth Lundstrom
Keyword(s):  
Dna Methylation ◽  
Drug Discovery ◽  
Rna Interference ◽  
Nutritional Requirements ◽  
Signal Pathways ◽  
Disease Development ◽  
Epigenetic Mechanisms ◽  
Epigenetic Changes ◽  
Health And Disease ◽  
Novel Drug

Epigenetic mechanisms comprising of DNA methylation, histone modifications and gene silencing by RNA interference have been strongly linked to the development and progression of various diseases. These findings have triggered research on epigenetic functions and signal pathways as targets for novel drug discovery. Dietary intake has also presented significant influence on human health and disease development and nutritional modifications have proven important in prevention, but also the treatment of disease. Moreover, a strong link between nutrition and epigenetic changes has been established. Therefore, in attempts to develop novel safer and more efficacious drugs, both nutritional requirements and epigenetic mechanisms need to be addressed.

Epigenetic Studies in Psychotherapy: A Systematic Review

2020 ◽  
Vol 16 (2) ◽  
pp. 86-92
Author(s):  
Rafael Penadés ◽  
Bárbara Arias ◽  
Mar Fatjó-Vilas ◽  
Laura González-Vallespí ◽  
Clemente García-Rizo ◽  
...  
Keyword(s):  
Systematic Review ◽  
Dna Methylation ◽  
Mental Disorders ◽  
Epigenetic Modifications ◽  
Symptom Improvement ◽  
Epigenetic Changes ◽  
Main Hypothesis ◽  
Psychological Treatments ◽  
Time Period ◽  
The Impact

Background: Epigenetic modifications appear to be dynamic and they might be affected by environmental factors. The possibility of influencing these processes through psychotherapy has been suggested. Objective: To analyse the impact of psychotherapy on epigenetics when applied to mental disorders. The main hypothesis is that psychological treatments will produce epigenetic modifications related to the improvement of treated symptoms. Methods: A computerised and systematic search was completed throughout the time period from 1990 to 2019 on the PubMed, ScienceDirect and Scopus databases. Results: In total, 11 studies were selected. The studies were evaluated for the theoretical framework, genes involved, type of psychotherapy and clinical challenges and perspectives. All studies showed detectable changes at the epigenetic level, like DNA methylation changes, associated with symptom improvement after psychotherapy. Conclusion: Methylation profiles could be moderating treatment effects of psychotherapy. Beyond the detected epigenetic changes after psychotherapy, the epigenetic status before the implementation could act as an effective predictor of response.

scholarly journals Cancer Epigenetics: New Therapies and New Challenges

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Eleftheria Hatzimichael ◽  
Tim Crook
Keyword(s):  
Dna Methylation ◽  
Epigenetic Modification ◽  
Hdac Inhibitors ◽  
Clinical Impact ◽  
Clinical Use ◽  
Cancer Epigenetics ◽  
Dnmt Inhibitors ◽  
Epigenetic Effects ◽  
New Challenges ◽  
Neoplastic Disorders

Cancer is nowadays considered to be both a genetic and an epigenetic disease. The most well studied epigenetic modification in humans is DNA methylation; however it becomes increasingly acknowledged that DNA methylation does not work alone, but rather is linked to other modifications, such as histone modifications. Epigenetic abnormalities are reversible and as a result novel therapies that work by reversing epigenetic effects are being increasingly explored. The biggest clinical impact of epigenetic modifying agents in neoplastic disorders thus far has been in haematological malignancies, and the efficacy of DNMT inhibitors and HDAC inhibitors in blood cancers clearly attests to the principle that therapeutic modification of the cancer cell epigenome can produce clinical benefit. This paper will discuss the most well studied epigenetic modifications and how these are linked to cancer, will give a brief overview of the clinical use of epigenetics as biomarkers, and will focus in more detail on epigenetic drugs and their use in solid and blood cancers.

scholarly journals Gene expression and DNA methylation analyses suggest that two immune related genes are prognostic factors of colorectal cancer

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Xiao-Liang Xing ◽  
Zhi-Yong Yao ◽  
Chaoqun Xing ◽  
Zhi Huang ◽  
Jing Peng ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Risk Assessment ◽  
Dna Methylation ◽  
Differentially Expressed Genes ◽  
Risk Score ◽  
Immune Cells ◽  
Assessment Model ◽  
Differentially Expressed ◽  
Risk Assessment Model

Abstract Background Colorectal cancer (CRC) is the second most prevalent cancer, as it accounts for approximately 10% of all annually diagnosed cancers. Studies have indicated that DNA methylation is involved in cancer genesis. The purpose of this study was to investigate the relationships among DNA methylation, gene expression and the tumor-immune microenvironment of CRC, and finally, to identify potential key genes related to immune cell infiltration in CRC. Methods In the present study, we used the ChAMP and DESeq2 packages, correlation analyses, and Cox regression analyses to identify immune-related differentially expressed genes (IR-DEGs) that were correlated with aberrant methylation and to construct a risk assessment model. Results Finally, we found that HSPA1A expression and CCRL2 expression were positively and negatively associated with the risk score of CRC, respectively. Patients in the high-risk group were more positively correlated with some types of tumor-infiltrating immune cells, whereas they were negatively correlated with other tumor-infiltrating immune cells. After the patients were regrouped according to the median risk score, we could more effectively distinguish them based on survival outcome, clinicopathological characteristics, specific tumor-immune infiltration status and highly expressed immune-related biomarkers. Conclusion This study suggested that the risk assessment model constructed by pairing immune-related differentially expressed genes correlated with aberrant DNA methylation could predict the outcome of CRC patients and might help to identify those patients who could benefit from antitumor immunotherapy.

Impact of depression and stress on placental DNA methylation in ethnically diverse pregnant women

Epigenomics ◽  
2021 ◽  
Author(s):  
Markos Tesfaye ◽  
Suvo Chatterjee ◽  
Xuehuo Zeng ◽  
Paule Joseph ◽  
Fasil Tekola-Ayele
Keyword(s):  
Dna Methylation ◽  
Fetal Brain ◽  
Ethnically Diverse ◽  
Antenatal Depression ◽  
Epigenetic Changes ◽  
Clinical Trial Registration ◽  
False Discovery ◽  
Genome Wide ◽  
Neuropsychiatric Diseases ◽  
Registration Number

Aim: To investigate the association between placental genome-wide methylation at birth and antenatal depression and stress during pregnancy. Methods: We examined the association between placental genome-wide DNA methylation (n = 301) and maternal depression and stress assessed at six gestation periods during pregnancy. Correlation between DNA methylation at the significantly associated CpGs and expression of nearby genes in the placenta was tested. Results: Depression and stress were associated with methylation of 16 CpGs and two CpGs, respectively, at a 5% false discovery rate. Methylation levels at two of the CpGs associated with depression were significantly associated with expression of ADAM23 and CTDP1, genes implicated in neurodevelopment and neuropsychiatric diseases. Conclusion: Placental epigenetic changes linked to antenatal depression suggest potential fetal brain programming. Clinical trial registration number: NCT00912132 (ClinicalTrials.gov)

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