scholarly journals Whole Genome Methylation Analysis Reveals Role of DNA Methylation in Cow’s Ileal and Ileal Lymph Node Responses to Mycobacterium avium subsp. paratuberculosis Infection

2021 ◽  
Vol 12 ◽  
Author(s):  
Eveline M. Ibeagha-Awemu ◽  
Nathalie Bissonnette ◽  
Suraj Bhattarai ◽  
Mengqi Wang ◽  
Pier-Luc Dudemaine ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Immune Response ◽  
Lymph Node ◽  
Whole Genome ◽  
Metabolic Processes ◽  
Cellular Processes ◽  
Gut Immunity ◽  
Mycobacterium Avium Subsp Paratuberculosis ◽  
Go Terms

Johne’s Disease (JD), caused by Mycobacterium avium subsp paratuberculosis (MAP), is an incurable disease of ruminants and other animal species and is characterized by an imbalance of gut immunity. The role of MAP infection on the epigenetic modeling of gut immunity during the progression of JD is still unknown. This study investigated the DNA methylation patterns in ileal (IL) and ileal lymph node (ILLN) tissues from cows diagnosed with persistent subclinical MAP infection over a one to 4 years period. DNA samples from IL and ILLN tissues from cows negative (MAPneg) (n = 3) or positive for MAP infection (MAPinf) (n = 4) were subjected to whole genome bisulfite sequencing. A total of 11,263 and 62,459 differentially methylated cytosines (DMCs), and 1259 and 8086 differentially methylated regions (DMRs) (FDR<0.1) were found between MAPinf and MAPneg IL and ILLN tissues, respectively. The DMRs were found on 394 genes (denoted DMR genes) in the IL and on 1305 genes in the ILLN. DMR genes with hypermethylated promoters/5′UTR [3 (IL) and 88 (ILLN)] or hypomethylated promoters/5′UTR [10 (IL) and 25 (ILLN)] and having multiple functions including response to stimulus/immune response (BLK, BTC, CCL21, AVPR1A, CHRNG, GABRA4, TDGF1), cellular processes (H2AC20, TEX101, GLA, NCKAP5L, RBM27, SLC18A1, H2AC20BARHL2, NLGN3, SUV39H1, GABRA4, PPA1, UBE2D2) and metabolic processes (GSTO2, H2AC20, SUV39H1, PPA1, UBE2D2) are potential DNA methylation candidate genes of MAP infection. The ILLN DMR genes were enriched for more biological process (BP) gene ontology (GO) terms (n = 374), most of which were related to cellular processes (27.6%), biological regulation (16.6%), metabolic processes (15.4%) and response to stimulus/immune response (8.2%) compared to 75 BP GO terms (related to cellular processes, metabolic processes and transport, and system development) enriched for IL DMR genes. ILLN DMR genes were enriched for more pathways (n = 47) including 13 disease pathways compared with 36 enriched pathways, including 7 disease/immune pathways for IL DMR genes. In conclusion, the results show tissue specific responses to MAP infection with more epigenetic changes (DMCs and DMRs) in the ILLN than in the IL tissue, suggesting that the ILLN and immune processes were more responsive to regulation by methylation of DNA relative to IL tissue. Our data is the first to demonstrate a potential role for DNA methylation in the pathogenesis of MAP infection in dairy cattle.

scholarly journals 63 DNA methylome wide profile associates differentially methylated loci and regions with cow’s ileal lymph node response to Mycobacterium avium subsp. paratuberculosis

2020 ◽  
Vol 98 (Supplement_4) ◽  
pp. 39-40
Author(s):  
Eveline M Ibeagha-Awemu ◽  
Suraj Bhattarai ◽  
Pier-Luc Dedemaine ◽  
Mengqi Wang ◽  
Stephanie D McKay ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Lymph Node ◽  
Immune Responses ◽  
Signaling Pathway ◽  
Cell Receptor ◽  
Negative Regulation ◽  
Term Survival ◽  
Host Immune Responses ◽  
Mycobacterium Avium Subsp Paratuberculosis

Abstract Johne’s Disease (JD), caused by Mycobacterium avim spp paratuberculosis (MAP), is a chronic and incurable disease of ruminants with devastating consequences to the dairy industry. MAP can alter the expression of genes and biological processes during the progression of JD. While some studies have examined the role of gene expression regulators like microRNA in the pathogenesis of JD, no study has explored the role of DNA methylation. This study therefore examined the effect of MAP on DNA methylation profile in the ileum lymph node (ILLN) of cows with subclinical MAP infection. DNA from ILLN tissues from five cows positive for MAP (MAP positive) and five negative cows (MAP negative) were extracted and subjected to whole genome bisulfite sequencing and bioinformatics analysis. A total of 6,394 differentially methylated cytosines (DMCs) and 3,946 differentially methylated regions (DMRs) (FDR < 0.05) were identified between MAP positive and negative cows. DMRs were annotated to 2,488 genes, including the promoters of 238 genes. Some genes with hypermethylated promoters like GRB10, EIF4E, SLC30A3, SOX30 or hypomethylated promoters like SLC11A1, HOXA4, SLC18A1 have been associated with JD or mycobacterial infections in cattle and/or humans. Functional annotation of DMR genes indicated enrichment in pathways previously associated with JD or human diseases with similar pathological conditions as JD, such as T/B cell receptor signaling pathway, Th17 cell differentiation, Cell adhesion molecules, Leukocyte transendothelial migration, HIF-1 signaling pathway and Chagas disease. Furthermore, enriched gene ontology terms like negative regulation of immune system process, negative regulation of cytokine secretion/production and negative regulation of inflammatory response suggest that MAP prevented or reduced the host immune response. Our data demonstrate that DNA methylation changes contribute to regulation of host immune responses to MAP infection and may be one of the mechanisms that MAP uses to subvert host immune responses for its long-term survival.

scholarly journals Role of Virally-Encoded Deubiquitinating Enzymes in Regulation of the Virus Life Cycle

2021 ◽  
Vol 22 (9) ◽  
pp. 4438
Author(s):  
Jessica Proulx ◽  
Kathleen Borgmann ◽  
In-Woo Park
Keyword(s):  
Immune Response ◽  
Life Cycle ◽  
Deubiquitinating Enzyme ◽  
Deubiquitinating Enzymes ◽  
Antiviral Immune Response ◽  
Cellular Processes ◽  
Virus Life Cycle ◽  
Infected Cells ◽  
Dependent Processes

The ubiquitin (Ub) proteasome system (UPS) plays a pivotal role in regulation of numerous cellular processes, including innate and adaptive immune responses that are essential for restriction of the virus life cycle in the infected cells. Deubiquitination by the deubiquitinating enzyme, deubiquitinase (DUB), is a reversible molecular process to remove Ub or Ub chains from the target proteins. Deubiquitination is an integral strategy within the UPS in regulating survival and proliferation of the infecting virus and the virus-invaded cells. Many viruses in the infected cells are reported to encode viral DUB, and these vial DUBs actively disrupt cellular Ub-dependent processes to suppress host antiviral immune response, enhancing virus replication and thus proliferation. This review surveys the types of DUBs encoded by different viruses and their molecular processes for how the infecting viruses take advantage of the DUB system to evade the host immune response and expedite their replication.

scholarly journals Cellular and molecular changes and immune response in the intestinal mucosa during Trichinella spiralis early infection in rats

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
María Priscila Saracino ◽  
Cecilia Celeste Vila ◽  
Melina Cohen ◽  
María Virginia Gentilini ◽  
Guido Hernán Falduto ◽  
...  
Keyword(s):  
Immune Response ◽  
Lamina Propria ◽  
Trichinella Spiralis ◽  
Mucosal Immune Response ◽  
Mesenteric Lymph Nodes ◽  
Muscle Larvae ◽  
Gut Immunity ◽  
Gut Mucosa

Abstract Background: The main targets of the host’s immune system in Trichinella spiralis infection are the adult worms (AW), at the gut level, and the migrant or newborn larvae (NBL), at systemic and pulmonary levels. Most of the studies carried out in the gut mucosa have been performed on the Payer’s patches and/or the mesenteric lymph nodes but not on the lamina propria, therefore, knowledge on the gut immune response against T. spiralis remains incomplete. Methods This study aimed at characterizing the early mucosal immune response against T. spiralis, particularly, the events taking place between 1 and 13 dpi. For this purpose, Wistar rats were orally infected with muscle larvae of T. spiralis and the humoral and cellular parameters of the gut immunity were analysed, including the evaluation of the ADCC mechanism exerted by lamina propria cells. Results A marked inflammation and structural alteration of the mucosa was found. The changes involved an increase in goblet cells, eosinophils and mast cells, and B and T lymphocytes, initially displaying a Th1 profile, characterised by the secretion of IFN-γ and IL-12, followed by a polarization towards a Th2 profile, with a marked increase in IgE, IgG1, IL-4, IL-5 and IL-13 levels, which occurred once the infection was established. In addition, the helminthotoxic activity of lamina propria cells demonstrated the role of the intestine as a place of migrant larvae destruction, indicating that not all the NBLs released in the gut will be able to reach the muscles. Conclusions The characterization of the immune response triggered in the gut mucosa during T. spiralis infection showed that not only an effector mechanism is directed toward the AW but also towards the NBL as a cytotoxic activity was observed against NBL exerted by lamina propria cells.

scholarly journals Evolutionary and functional genomics of DNA methylation in maize domestication and improvement

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Gen Xu ◽  
Jing Lyu ◽  
Qing Li ◽  
Han Liu ◽  
Dafang Wang ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Direct Selection ◽  
Whole Genome ◽  
Evolutionary Forces ◽  
Weak Evidence ◽  
Modern Maize ◽  
Genome Bisulfite Sequencing ◽  
Maize Domestication ◽  
Chromatin Feature

Abstract DNA methylation is a ubiquitous chromatin feature, present in 25% of cytosines in the maize genome, but variation and evolution of the methylation landscape during maize domestication remain largely unknown. Here, we leverage whole-genome sequencing (WGS) and whole-genome bisulfite sequencing (WGBS) data on populations of modern maize, landrace, and teosinte (Zea mays ssp. parviglumis) to estimate epimutation rates and selection coefficients. We find weak evidence for direct selection on DNA methylation in any context, but thousands of differentially methylated regions (DMRs) are identified population-wide that are correlated with recent selection. For two trait-associated DMRs, vgt1-DMR and tb1-DMR, HiChIP data indicate that the interactive loops between DMRs and respective downstream genes are present in B73, a modern maize line, but absent in teosinte. Our results enable a better understanding of the evolutionary forces acting on patterns of DNA methylation and suggest a role of methylation variation in adaptive evolution.

scholarly journals ARPEGGIO: Automated Reproducible Polyploid EpiGenetic GuIdance workflOw

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Stefan Milosavljevic ◽  
Tony Kuo ◽  
Samuele Decarli ◽  
Lucas Mohn ◽  
Jun Sese ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Molecular Mechanisms ◽  
Sequence Similarity ◽  
Ground Truth ◽  
Whole Genome ◽  
Initial Dataset ◽  
Quality Checks ◽  
Living Organisms ◽  
Set Up

Abstract Background Whole genome duplication (WGD) events are common in the evolutionary history of many living organisms. For decades, researchers have been trying to understand the genetic and epigenetic impact of WGD and its underlying molecular mechanisms. Particular attention was given to allopolyploid study systems, species resulting from an hybridization event accompanied by WGD. Investigating the mechanisms behind the survival of a newly formed allopolyploid highlighted the key role of DNA methylation. With the improvement of high-throughput methods, such as whole genome bisulfite sequencing (WGBS), an opportunity opened to further understand the role of DNA methylation at a larger scale and higher resolution. However, only a few studies have applied WGBS to allopolyploids, which might be due to lack of genomic resources combined with a burdensome data analysis process. To overcome these problems, we developed the Automated Reproducible Polyploid EpiGenetic GuIdance workflOw (ARPEGGIO): the first workflow for the analysis of epigenetic data in polyploids. This workflow analyzes WGBS data from allopolyploid species via the genome assemblies of the allopolyploid’s parent species. ARPEGGIO utilizes an updated read classification algorithm (EAGLE-RC), to tackle the challenge of sequence similarity amongst parental genomes. ARPEGGIO offers automation, but more importantly, a complete set of analyses including spot checks starting from raw WGBS data: quality checks, trimming, alignment, methylation extraction, statistical analyses and downstream analyses. A full run of ARPEGGIO outputs a list of genes showing differential methylation. ARPEGGIO was made simple to set up, run and interpret, and its implementation ensures reproducibility by including both package management and containerization. Results We evaluated ARPEGGIO in two ways. First, we tested EAGLE-RC’s performance with publicly available datasets given a ground truth, and we show that EAGLE-RC decreases the error rate by 3 to 4 times compared to standard approaches. Second, using the same initial dataset, we show agreement between ARPEGGIO’s output and published results. Compared to other similar workflows, ARPEGGIO is the only one supporting polyploid data. Conclusions The goal of ARPEGGIO is to promote, support and improve polyploid research with a reproducible and automated set of analyses in a convenient implementation. ARPEGGIO is available at https://github.com/supermaxiste/ARPEGGIO.

scholarly journals BoostMe accurately predicts DNA methylation values in whole-genome bisulfite sequencing of multiple human tissues

2017 ◽  
Author(s):  
Luli S. Zou ◽  
Michael R. Erdos ◽  
D. Leland Taylor ◽  
Peter S. Chines ◽  
Arushi Varshney ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Bisulfite Sequencing ◽  
Gradient Boosting ◽  
Whole Genome ◽  
Human Tissues ◽  
Whole Genome Bisulfite Sequencing ◽  
Genome Bisulfite Sequencing ◽  
Boosting Algorithm ◽  
Multiple Samples

AbstractBisulfite sequencing is widely employed to study the role of DNA methylation in disease; however, the data suffer from biases due to coverage depth variability. Here we describe BoostMe, a method for imputing low quality DNA methylation estimates within whole-genome bisulfite sequencing (WGBS) data. BoostMe uses a gradient boosting algorithm, XGBoost, and leverages information from multiple samples for prediction. We find that BoostMe outperforms existing algorithms in speed and accuracy when applied to WGBS of human tissues. We also show that imputation improves concordance between WGBS and the MethylationEPIC array at low WGBS depth, suggesting improved WGBS accuracy after imputation.

P–529 Whole-genome methylation analysis of testicular germ cells from cryptozoospermic men points to recurrent and functionally relevant DNA methylation changes

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
S D Persio ◽  
E Leitão ◽  
M Wöste ◽  
T Tekath ◽  
J F Cremers ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Germ Cell ◽  
Germ Cells ◽  
Small Sample ◽  
Global Dna Methylation ◽  
Obstructive Azoospermia ◽  
Whole Genome ◽  
Ploidy Analysis ◽  
Normal Spermatogenesis

Abstract Study question Do DNA methylation changes occur in testicular germ cells (TGCs) from patients with impaired spermatogenesis? Summary answer TGCs from men with cryptozoospermia exhibit altered DNA methylation levels at several genomic regions, many of which are associated with genes involved in spermatogenesis. What is known already In the last 15 years, several studies have described DNA methylation changes in sperm of infertile men. More recently, using whole genome bisulfite sequencing (WGBS) we were able to refute these findings by demonstrating that somatic DNA contamination and genetic variation confound methylation studies in swim-up purified sperm of severely oligozoospermic men. However, it remains unknown whether altered DNA methylation plays a role during the development of the germ cells in the testes of these patients. Study design, size, duration For identifying DNA methylation differences associated with impaired spermatogenesis, we compared the TGC methylomes of men with cryptozoospermia (CZ) and men with obstructive azoospermia (n = 4 each), who had normal spermatogenesis and served as controls (CTR). Study participants were selected among an age-matched cohort of 24 CTR and 10 CZ. The selection was based on similar composition of the TGC suspension evaluated by ploidy analysis and absence of somatic DNA. Participants/materials, setting, methods TGCs were isolated from biopsies after short-term cell culture. Presence of somatic DNA was evaluated by analyzing the DNA methylation levels of H19, MEST, DDX4 and XIST. WGBS was performed at ∼14× coverage. Bioinformatic tools were used to compare global DNA methylation levels, identify differentially methylated regions (DMRs) and functionally annotate the DMRs. Single-cell RNA sequencing (scRNA-seq) was used to associate the DNA methylation changes to gene expression. Main results and the role of chance We could not identify any difference in the global DNA methylation level or at imprinted regions between CZ and CTR samples. However, using stringent filters to identify group-specific methylation differences, we detected 271 DMRs, 238 of which were hypermethylated in CZ (binominal test, p < 2.2 × 10–16). The DMRs are associated with 132 genes, 61 of which are known to be differentially expressed at various stages of spermatogenesis according to scRNA-seq studies. Almost all of the DMRs associated with the 61 genes are hypermethylated in CZ (63/67, p = 1.107 × 10–14). As assessed by scRNA-seq, 13 DMR-associated genes, which were mainly expressed during meiosis and spermiogenesis, show a significantly different pattern of expression in CZ patients. In four of these genes, the promoter was hypermethylated in CZ men, which correlates with a lower expression level in these patients. In the other nine genes, most of which downregulated in CZ, germ cell-specific enhancers may be affected. Limitations, reasons for caution The small sample size constitutes a limitation of this study. Furthermore, even though the cellular composition of samples was similar by ploidy analysis, we cannot rule out that the observed DNA methylation changes might be due to differences in the relative proportion of different germ cell types. Wider implications of the findings: Impaired spermatogenesis is associated with DNA methylation changes in testicular germ cells at functionally relevant regions of the genome, which points to an important role of DNA methylation in normal spermatogenesis. The DNA methylation changes may contribute to premature abortion of spermatogenesis and therefore not appear in mature sperm. Trial registration number N/A

scholarly journals L1 Antibodies Block Lymph Node Fibroblastic Reticular Matrix Remodeling In Vivo

1998 ◽  
Vol 187 (12) ◽  
pp. 1953-1963 ◽  
Author(s):  
Gino Di Sciullo ◽  
Tim Donahue ◽  
Melitta Schachner ◽  
Steven A. Bogen
Keyword(s):  
Immune Response ◽  
Lymph Node ◽  
Primary Immune Response ◽  
Immunoglobulin Superfamily ◽  
Matrix Remodeling ◽  
Protein Antigens ◽  
Cellular Processes ◽  
Reticular System ◽  
Macrophage Accumulation

L1 is an immunoglobulin superfamily adhesion molecule highly expressed on neurons and involved in cell motility, neurite outgrowth, axon fasciculation, myelination, and synaptic plasticity. L1 is also expressed by nonneural cells, but its function outside of the nervous system has not been studied extensively. We find that administration of an L1 monoclonal antibody in vivo disrupts the normal remodeling of lymph node reticular matrix during an immune response. Ultrastructural examination reveals that reticular fibroblasts in mice treated with L1 monoclonal antibodies fail to spread and envelop collagen fibers with their cellular processes. The induced defect in the remodeling of the fibroblastic reticular system results in the loss of normal nodal architecture, collapsed cortical sinusoids, and macrophage accumulation in malformed sinuses. Surprisingly, such profound architectural abnormalities have no detectable effects on the primary immune response to protein antigens.

scholarly journals The Role of Host Cell DNA Methylation in the Immune Response to Bacterial Infection

2021 ◽  
Vol 12 ◽  
Author(s):  
Wanhai Qin ◽  
Brendon P. Scicluna ◽  
Tom van der Poll
Keyword(s):  
Dna Methylation ◽  
Immune Response ◽  
Bacterial Infection ◽  
Epigenetic Modification ◽  
Dna Methyltransferases ◽  
Host Cells ◽  
Regulate Gene Expression ◽  
Transcriptional Reprogramming ◽  
Methylation Patterns

Host cells undergo complex transcriptional reprogramming upon infection. Epigenetic changes play a key role in the immune response to bacteria, among which DNA modifications that include methylation have received much attention in recent years. The extent of DNA methylation is well known to regulate gene expression. Whilst historically DNA methylation was considered to be a stable epigenetic modification, accumulating evidence indicates that DNA methylation patterns can be altered rapidly upon exposure of cells to changing environments and pathogens. Furthermore, the action of proteins regulating DNA methylation, particularly DNA methyltransferases and ten-eleven translocation methylcytosine dioxygenases, may be modulated, at least in part, by bacteria. This review discusses the principles of DNA methylation, and recent insights about the regulation of host DNA methylation during bacterial infection.

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