scholarly journals DNA Methylation of Fibroblast Phenotypes and Contributions to Lung Fibrosis

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1977
Author(s):  
Poojitha Rajasekar ◽  
Jamie Patel ◽  
Rachel L. Clifford
Keyword(s):  
Dna Methylation ◽  
Lung Disease ◽  
Primary Source ◽  
Lung Fibroblast ◽  
Bioactive Molecules ◽  
Lung Fibroblasts ◽  
Covalent Attachment ◽  
Immune Functions ◽  
Cellular Origin ◽  
Cellular Phenotypes

Fibroblasts are an integral part of connective tissue and play a crucial role in developing and modulating the structural framework of tissues by acting as the primary source of extracellular matrix (ECM). A precise definition of the fibroblast remains elusive. Lung fibroblasts orchestrate the assembly and turnover of ECM to facilitate gas exchange alongside performing immune functions including the secretion of bioactive molecules and antigen presentation. DNA methylation is the covalent attachment of a methyl group to primarily cytosines within DNA. DNA methylation contributes to diverse cellular phenotypes from the same underlying genetic sequence, with DNA methylation profiles providing a memory of cellular origin. The lung fibroblast population is increasingly viewed as heterogeneous with between 6 and 11 mesenchymal populations identified across health and lung disease to date. DNA methylation has been associated with different lung fibroblast populations in health and with alterations in lung disease, but to varying extents. In this review, we will discuss lung fibroblast heterogeneity and the evidence for a contribution from DNA methylation to defining cell populations and alterations in disease.

scholarly journals DNA Methylation Profiling for the Diagnosis and Prognosis of Patients with Nontuberculous Mycobacterium Lung Disease

2021 ◽  
Vol 43 (2) ◽  
pp. 501-512
Author(s):  
Jee Youn Oh ◽  
Young Kyung Ko ◽  
Jeong-An Gim
Keyword(s):  
Dna Methylation ◽  
Lung Disease ◽  
Poor Prognosis ◽  
Wnt Signaling Pathway ◽  
Fold Change ◽  
Nontuberculous Mycobacterium ◽  
Healthy Controls ◽  
Log2 Fold Change ◽  
Diagnosis And Prognosis ◽  
Ntm Lung Disease

The incidence of nontuberculous Mycobacterium (NTM) lung disease is rapidly increasing; however, its diagnosis and prognosis remain unclear while selecting patients who will respond to appropriate treatment. Differences in DNA methylation patterns between NTM patients with good or poor prognosis could provide important therapeutic targets. We used the Illumina MethylationEPIC (850k) DNA methylation microarray to determine the pattern between differentially methylated regions (DMRs) in NTM patients with good or poor prognosis (n = 4/group). Moreover, we merged and compared 20 healthy controls from previous Illumina Methylation450k DNA methylation microarray data. We selected and visualized the DMRs in the form of heatmaps, and enriched terms associated with these DMRs were identified by functional annotation with the “pathfinder” package. In total, 461 and 293 DMRs (|Log2 fold change| > 0.1 and p < 0.03) were more methylated in patients with four poor and four good prognoses, respectively. Furthermore, 337 and 771 DMRs (|Log2 fold change| > 0.08 and p < 0.001) were more methylated in eight NTM patients and 20 healthy controls, respectively. TGFBr1 was significantly less methylated, whereas HLA-DR1 and HLA-DR5 were more methylated in patients with poor prognosis (compared to those with good prognosis). LRP5, E2F1, and ADCY3 were the top three less-methylated genes in NTM patients (compared with the controls). The mTOR and Wnt signaling pathway-related genes were less methylated in patients with NTM. Collectively, genes related to Th1-cell differentiation, such as TGFBr1 and HLA-DR, may be used as biomarkers for predicting the treatment response in patients with NTM lung disease.

scholarly journals DNA Methylation at ATP11A cg11702988 Is a Biomarker of Lung Disease Severity in Cystic Fibrosis: A Longitudinal Study

Genes ◽  
2021 ◽  
Vol 12 (3) ◽  
pp. 441
Author(s):  
Fanny Pineau ◽  
Davide Caimmi ◽  
Sylvie Taviaux ◽  
Maurane Reveil ◽  
Laura Brosseau ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Dna Methylation ◽  
Clinical Trials ◽  
Lung Disease ◽  
Disease Severity ◽  
Genome Wide ◽  
A Genome ◽  
Lung Disease Severity ◽  
Epigenetic Biomarker

Cystic fibrosis (CF) is a chronic genetic disease that mainly affects the respiratory and gastrointestinal systems. No curative treatments are available, but the follow-up in specialized centers has greatly improved the patient life expectancy. Robust biomarkers are required to monitor the disease, guide treatments, stratify patients, and provide outcome measures in clinical trials. In the present study, we outline a strategy to select putative DNA methylation biomarkers of lung disease severity in cystic fibrosis patients. In the discovery step, we selected seven potential biomarkers using a genome-wide DNA methylation dataset that we generated in nasal epithelial samples from the MethylCF cohort. In the replication step, we assessed the same biomarkers using sputum cell samples from the MethylBiomark cohort. Of interest, DNA methylation at the cg11702988 site (ATP11A gene) positively correlated with lung function and BMI, and negatively correlated with lung disease severity, P. aeruginosa chronic infection, and the number of exacerbations. These results were replicated in prospective sputum samples collected at four time points within an 18-month period and longitudinally. To conclude, (i) we identified a DNA methylation biomarker that correlates with CF severity, (ii) we provided a method to easily assess this biomarker, and (iii) we carried out the first longitudinal analysis of DNA methylation in CF patients. This new epigenetic biomarker could be used to stratify CF patients in clinical trials.

scholarly journals Cell-to-Cell Communication by Host-Released Extracellular Vesicles in the Gut: Implications in Health and Disease

2021 ◽  
Vol 22 (4) ◽  
pp. 2213
Author(s):  
Natalia Diaz-Garrido ◽  
Cecilia Cordero ◽  
Yenifer Olivo-Martinez ◽  
Josefa Badia ◽  
Laura Baldomà
Keyword(s):  
Extracellular Vesicles ◽  
Intestinal Mucosa ◽  
Current Knowledge ◽  
Cell Communication ◽  
Bioactive Molecules ◽  
Target Cells ◽  
Immune Functions ◽  
Intestinal Homeostasis ◽  
General Terms ◽  
Health And Disease

Communication between cells is crucial to preserve body homeostasis and health. Tightly controlled intercellular dialog is particularly relevant in the gut, where cells of the intestinal mucosa are constantly exposed to millions of microbes that have great impact on intestinal homeostasis by controlling barrier and immune functions. Recent knowledge involves extracellular vesicles (EVs) as mediators of such communication by transferring messenger bioactive molecules including proteins, lipids, and miRNAs between cells and tissues. The specific functions of EVs principally depend on the internal cargo, which upon delivery to target cells trigger signal events that modulate cellular functions. The vesicular cargo is greatly influenced by genetic, pathological, and environmental factors. This finding provides the basis for investigating potential clinical applications of EVs as therapeutic targets or diagnostic biomarkers. Here, we review current knowledge on the biogenesis and cargo composition of EVs in general terms. We then focus the attention to EVs released by cells of the intestinal mucosa and their impact on intestinal homeostasis in health and disease. We specifically highlight their role on epithelial barrier integrity, wound healing of epithelial cells, immunity, and microbiota shaping. Microbiota-derived EVs are not reviewed here.

Surfactant downregulates synthesis of DNA and inflammatory mediators in normal human lung fibroblasts

1996 ◽  
Vol 270 (1) ◽  
pp. L159-L163 ◽  
Author(s):  
M. J. Thomassen ◽  
J. M. Antal ◽  
B. P. Barna ◽  
L. T. Divis ◽  
D. P. Meeker ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Inflammatory Mediators ◽  
Human Lung ◽  
Thymidine Incorporation ◽  
Interleukin 1 ◽  
S Phase ◽  
Lung Fibroblast ◽  
Lung Fibroblasts ◽  
Human Lung Fibroblast ◽  
Normal Human

The initial inflammatory event in the adult respiratory distress syndrome (ARDS) is followed by fibroproliferation and a cascade of fibroblast-derived mediators. Because lung fibroblasts may be exposed to surfactant as well as inflammatory cytokines during ARDS, we hypothesized that surfactant might modulate fibroblast activity. We previously demonstrated that surfactant inhibited production of inflammatory cytokines from endotoxin-stimulated human alveolar macrophages. In the current study the effects of surfactant on normal human lung fibroblast proliferative capacity and mediator production were examined. Both synthetic (Exosurf) and natural (Survanta) surfactant inhibited fibroblast [3H]thymidine incorporation. Examination of pre-S-phase events indicated stimulation of the immediate response gene, c-fos, and no effect on the G1/S cyclin, cyclin D1, suggesting that the surfactant block occurred elsewhere before S phase. The antioxidant N-acetyl-L-cysteine (NAC), like surfactant, inhibited [3H]thymidine incorporation. Furthermore, menadione, a generator of intracellular H2O2, stimulated fibroblast [3H]thymidine incorporation, and this was inhibited by surfactant. Interleukin-1 (IL-1)-stimulated secretion of the inflammatory mediators, IL-6 and prostaglandin E2, was also inhibited by surfactant. These data suggest that surfactant may modify lung fibroblast participation in ARDS sequelae by downregulating DNA synthesis and secondary inflammatory mediator production.

scholarly journals P-Rex1 Cooperates With TGFβR2 to Drive Lung Fibroblast Migration in Pulmonary Fibrosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Qing Liang ◽  
Yanhua Chang ◽  
Jing Liu ◽  
Yan Yu ◽  
Wancheng Qiu ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Lung Fibroblast ◽  
Alveolar Epithelial Cells ◽  
Lung Fibroblasts ◽  
Mouse Lung ◽  
Nucleotide Exchange ◽  
Alveolar Epithelial ◽  
Fibroblast Migration ◽  
Overexpression System ◽  
Tgf Β1

Pulmonary fibrosis is a kind of interstitial lung disease with progressive pulmonary scar formation, leading to irreversible loss of lung functions. The TGF-β1/Smad signaling pathway plays a key role in fibrogenic processes. It is associated with the increased synthesis of extracellular matrix, enhanced proliferation of fibroblasts, and transformation of alveolar epithelial cells into interstitial cells. We investigated P-Rex1, a PIP3-Gβγ–dependent guanine nucleotide exchange factor (GEF) for Rac, for its potential role in TGF-β1–induced pulmonary fibrosis. A high expression level of P-Rex1 was identified in the lung tissue of patients with pulmonary fibrosis than that from healthy donors. Using the P-Rex1 knockdown and overexpression system, we established a novel player of P-Rex1 in mouse lung fibroblast migration. P-Rex1 contributed to fibrogenic processes in lung fibroblasts by targeting the TGF-β type Ⅱ receptor (TGFβR2). The RNA-seq analysis for expression profiling confirmed the modulation of P-Rex1 in cell migration and the involvement of P-Rex1 in TGF-β1 signaling. These results identified P-Rex1 as a signaling molecule involved in TGF-β1–induced pulmonary fibrosis, suggesting that P-Rex1 may be a potential target for pulmonary fibrosis treatment.

scholarly journals The Impact of Natural Dietary Compounds and Food-Borne Mycotoxins on DNA Methylation and Cancer

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 2004 ◽  
Author(s):  
Terisha Ghazi ◽  
Thilona Arumugam ◽  
Ashmika Foolchand ◽  
Anil A. Chuturgoon
Keyword(s):  
Dna Methylation ◽  
Bioactive Compounds ◽  
Epigenetic Modification ◽  
Bioactive Molecules ◽  
Methyl Donors ◽  
Food Borne ◽  
One Carbon Metabolism ◽  
Aberrant Dna Methylation ◽  
Methylation Patterns ◽  
The Impact

Cancer initiation and progression is an accumulation of genetic and epigenetic modifications. DNA methylation is a common epigenetic modification that regulates gene expression, and aberrant DNA methylation patterns are considered a hallmark of cancer. The human diet is a source of micronutrients, bioactive molecules, and mycotoxins that have the ability to alter DNA methylation patterns and are thus a contributing factor for both the prevention and onset of cancer. Micronutrients such as betaine, choline, folate, and methionine serve as cofactors or methyl donors for one-carbon metabolism and other DNA methylation reactions. Dietary bioactive compounds such as curcumin, epigallocatechin-3-gallate, genistein, quercetin, resveratrol, and sulforaphane reactivate essential tumor suppressor genes by reversing aberrant DNA methylation patterns, and therefore, they have shown potential against various cancers. In contrast, fungi-contaminated agricultural foods are a source of potent mycotoxins that induce carcinogenesis. In this review, we summarize the existing literature on dietary micronutrients, bioactive compounds, and food-borne mycotoxins that affect DNA methylation patterns and identify their potential in the onset and treatment of cancer.

Impaired HSF1 transactivation drives proteostasis collapse and senescent phenotype of IPF lung fibroblast

2020 ◽  
Author(s):  
Karina Cuevas-Mora ◽  
Willy Roque ◽  
Dominic Sales ◽  
Jeffrey D. Ritzenthaler ◽  
Edilson Torres-Gonzales ◽  
...  
Keyword(s):  
Heat Shock ◽  
Cellular Senescence ◽  
Lung Fibrosis ◽  
Smooth Muscle Actin ◽  
Lung Fibroblast ◽  
Lung Fibroblasts ◽  
Mouse Lung ◽  
Secretory Proteins ◽  
Heat Shock Factor 1 ◽  
Alpha Smooth Muscle Actin

ABSTRACTLoss of proteostasis and cellular senescence are key hallmarks of aging. Recent studies suggest that lung fibroblasts from idiopathic pulmonary fibrosis (IPF) show features of cellular senescence, decline in heat shock proteins (HSPs) expression and impaired protein homeostasis (proteostasis). However, direct cause-effect relationships are still mostly unknown. In this study, we sought to investigate whether the heat shock factor 1 (HSF1), a major transcription factor that regulates the cellular HSPs network and cytoplasmic proteostasis, contributes to cellular senescence in lung fibroblasts. We found that IPF lung fibroblasts showed an upregulation in the expression of various cellular senescence markers, including β-galactosidase activity (SA-β-gal) staining, the DNA damage marker γH2Ax, the cell cycle inhibitor protein p21, and multiple senescence-associated secretory proteins (SASP), as well as upregulation of collagen 1a1, fibronectin and alpha-smooth muscle actin (α-SMA) gene expression compared with age-matched controls. These changes were associated with impaired proteostasis, as judged by an increase in levels of p-HSF1ser307 and HSF1K298 sumo, downregulation of HSPs expression, and increased cellular protein aggregation. Similarly, lung fibroblasts isolated from a mouse model of bleomycin-induced lung fibrosis and mouse lung fibroblast chronically treated with H2O2 showed downregulation in HSPs and increased in cellular senescence and SASP markers. Moreover, sustained pharmacologic activation of HSF1 increased the expression of HSPs, reduced cellular senescence markers and effectively reduced the expression of pro-fibrotic genes in IPF fibroblast. Our data provide evidence that the HSF1-mediated proteostasis is important for driving lung fibroblasts toward cellular senescence and a myofibroblast phenotype. We postulate that enhancing HSF1 activity could be effective in the treatment of lung fibrosis.

Serine proteinase inhibitors influence the stability of tropoelastin mRNA in neonatal rat lung fibroblast cultures

1996 ◽  
Vol 270 (3) ◽  
pp. L376-L385
Author(s):  
S. E. McGowan ◽  
R. Liu ◽  
C. S. Harvey ◽  
E. C. Jaeckel
Keyword(s):  
Steady State ◽  
Culture Medium ◽  
Serine Proteinase ◽  
State Level ◽  
Lung Fibroblast ◽  
Neonatal Rat ◽  
Lung Fibroblasts ◽  
Steady State Level ◽  
Rat Lung ◽  
Fibroblast Cultures

Elastin, an elastic extracellular structural protein, is a polymer comprised of soluble tropoelastin (TE) monomers that are joined by covalent cross-links and become insoluble. In cultured vascular smooth muscle cells, the steady-state level of TE mRNA is influenced by soluble elastin moieties in the culture medium, either TE or its fragmentation products. We have hypothesized that an enzyme-mediated proteolytic event may modulate the quantities of TE and its fragmentation products in the culture medium of mesenchymal cells, and thereby indirectly regulate the steady-state level of TE mRNA. Neonatal rat lung fibroblasts were cultured in the presence or absence of the serine proteinase inhibitor, aprotinin, and the quantities of soluble elastin and TE mRNA were analyzed. Exposures to aprotinin lasting up to 12 h increased the soluble elastin content of the culture medium. The increase in the soluble elastin content did not reflect an increase in TE mRNA, which diminished after exposures for 12 h or longer. The decrease in TE mRNA resulted from a decrease in its half-life, rather than a decrease in the rate of TE gene transcription. Aprotinin did not reduce TE mRNA in plasminogen-depleted cultures, but the effect of aprotinin was evident when purified plasminogen was added back to the cultures. Therefore, a serine proteinase, possibly plasmin, may participate in a feedback mechanism and modulate the quantity of TE in lung fibroblast cultures. This mechanism may help ensure that intracellular TE synthesis occurs in tandem with extracellular elastin deposition and cross-linking.

scholarly journals DNA methyltransferase 1 and DNA methylation patterning contribute to germinal center B-cell differentiation

Blood ◽  
2011 ◽  
Vol 118 (13) ◽  
pp. 3559-3569 ◽  
Author(s):  
Rita Shaknovich ◽  
Leandro Cerchietti ◽  
Lucas Tsikitas ◽  
Matthias Kormaksson ◽  
Subhajyoti De ◽  
...  
Keyword(s):  
Dna Methylation ◽  
B Cells ◽  
Germinal Center ◽  
Dna Methyltransferase ◽  
Cytosine Deaminase ◽  
Dna Methyltransferases ◽  
B Cell Differentiation ◽  
Dual Roles ◽  
Germinal Center B Cell ◽  
Cellular Phenotypes

Abstract The phenotype of germinal center (GC) B cells includes the unique ability to tolerate rapid proliferation and the mutagenic actions of activation induced cytosine deaminase (AICDA). Given the importance of epigenetic patterning in determining cellular phenotypes, we examined DNA methylation and the role of DNA methyltransferases in the formation of GCs. DNA methylation profiling revealed a marked shift in DNA methylation patterning in GC B cells versus resting/naive B cells. This shift included significant differential methylation of 235 genes, with concordant inverse changes in gene expression affecting most notably genes of the NFkB and MAP kinase signaling pathways. GC B cells were predominantly hypomethylated compared with naive B cells and AICDA binding sites were highly overrepresented among hypomethylated loci. GC B cells also exhibited greater DNA methylation heterogeneity than naive B cells. Among DNA methyltransferases (DNMTs), only DNMT1 was significantly up-regulated in GC B cells. Dnmt1 hypomorphic mice displayed deficient GC formation and treatment of mice with the DNA methyltransferase inhibitor decitabine resulted in failure to form GCs after immune stimulation. Notably, the GC B cells of Dnmt1 hypomorphic animals showed evidence of increased DNA damage, suggesting dual roles for DNMT1 in DNA methylation and double strand DNA break repair.

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