DNA methylation changes in cystic fibrosis: Cause or consequence?

Scott, Madeleine; Sario, Albertina De

doi:10.1111/cge.13731

Cited by 11 publications

(8 citation statements)

References 30 publications

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“…Among noninheritable factors responsible for DNA methylation levels, there are lifestyle factors and, in the case of CF patients, the disease itself. Permanent and excessive inflammation, chronic exposure to bacterial infections, and exocrine pancreatic insufficiency can shape DNA methylation [34]. Methylation at the cg11702988 was low in two types of tissues from severe CF patients (nasal epithelial cell and sputum samples) and was stable overtime in sputum samples.…”

Section: Discussionmentioning

confidence: 99%

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

Pineau

Caimmi

Taviaux

et al. 2021

Genes

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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.

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Section: Discussionmentioning

confidence: 99%

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

Pineau

Caimmi

Taviaux

et al. 2021

Genes

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“…These events are known to be responsible for the establishment of unique DNA methylation profiles which modulate disease phenotype and severity. Altered methylation levels were already found in nasal epithelial and blood cell samples from CF patients [ 64 , 65 ]. We suppose that the altered lung environment in CF could affect the DNA methylation profile of stromal fibroblasts as well.…”

Section: Discussionmentioning

confidence: 99%

Intrinsic Abnormalities of Cystic Fibrosis Airway Connective Tissue Revealed by an In Vitro 3D Stromal Model

Mazio

Scognamiglio

Cegli

et al. 2020

Cells

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Cystic fibrosis is characterized by lung dysfunction involving mucus hypersecretion, bacterial infections, and inflammatory response. Inflammation triggers pro-fibrotic signals that compromise lung structure and function. At present, several in vitro cystic fibrosis models have been developed to study epithelial dysfunction but none of these focuses on stromal alterations. Here we show a new cystic fibrosis 3D stromal lung model made up of primary fibroblasts embedded in their own extracellular matrix and investigate its morphological and transcriptomic features. Cystic fibrosis fibroblasts showed a high proliferation rate and produced an abundant and chaotic matrix with increased protein content and elastic modulus. More interesting, they had enhanced pro-fibrotic markers and genes involved in epithelial function and inflammatory response. In conclusion, our study reveals that cystic fibrosis fibroblasts maintain in vitro an activated pro-fibrotic state. This abnormality may play in vivo a role in the modulation of epithelial and inflammatory cell behavior and lung remodeling. We argue that the proposed bioengineered model may provide new insights on epithelial/stromal/inflammatory cells crosstalk in cystic fibrosis, paving the way for novel therapeutic strategies.

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“…Global DNA methylation changes over the lifespan and methylation of specific CpG (cytosine guanine) sites correlate with age (Jones et al, 2015;Ashapkin et al, 2017;Levine et al, 2018). Alterations in DNA methylation patterns are associated with cancer, several genetic diseases and inflammatory lung conditions including CF (Robertson, 2005;Scott and De Sario, 2020). In CF, methylation changes were found at multiple CpG dinucleotides in nasal epithelial cells, whole blood and lung macrophages.…”

Section: Epigenetic Alterationsmentioning

confidence: 99%

“…In CF, methylation changes were found at multiple CpG dinucleotides in nasal epithelial cells, whole blood and lung macrophages. Interestingly, these epigenetic alterations were preferentially located at genes important for the respective tissue, such as for cell adhesion, immune response or inflammation, and correlated with lung function (Scott and De Sario, 2020;Magalhães et al, 2018;Chen et al, 2018). Though the specific research is yet in its infancy, CFTR has been shown to be epigenetically regulated too which may open up novel therapeutic strategies to restore CFTR dysfunction in CF pathology (Sirinupong and Yang, 2015).…”

Section: Epigenetic Alterationsmentioning

confidence: 99%

Cystic Fibrosis Lung Disease in the Aging Population

et al. 2021

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The demographics of the population with cystic fibrosis (CF) is continuously changing, with nowadays adults outnumbering children and a median predicted survival of over 40 years. This leads to the challenge of treating an aging CF population, while previous research has largely focused on pediatric and adolescent patients. Chronic inflammation is not only a hallmark of CF lung disease, but also of the aging process. However, very little is known about the effects of an accelerated aging pathology in CF lungs. Several chronic lung disease pathologies show signs of chronic inflammation with accelerated aging, also termed “inflammaging”; the most notable being chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). In these disease entities, accelerated aging has been implicated in the pathogenesis via interference with tissue repair mechanisms, alterations of the immune system leading to impaired defense against pulmonary infections and induction of a chronic pro-inflammatory state. In addition, CF lungs have been shown to exhibit increased expression of senescence markers. Sustained airway inflammation also leads to the degradation and increased turnover of cystic fibrosis transmembrane regulator (CFTR). This further reduces CFTR function and may prevent the novel CFTR modulator therapies from developing their full efficacy. Therefore, novel therapies targeting aging processes in CF lungs could be promising. This review summarizes the current research on CF in an aging population focusing on accelerated aging in the context of chronic airway inflammation and therapy implications.

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DNA methylation changes in cystic fibrosis: Cause or consequence?

Cited by 11 publications

References 30 publications

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

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

Intrinsic Abnormalities of Cystic Fibrosis Airway Connective Tissue Revealed by an In Vitro 3D Stromal Model

Cystic Fibrosis Lung Disease in the Aging Population

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