Disinherit your Descendants by Rewriting the Chronic Pulmonary Obstructive Disease Epigenetic Script

Chronic pulmonary obstructive disease (COPD) is a respiratory disease with a substantial burden on health care and the third leading cause of death globally. The development of the disease varies among the different patients, yet it is widely recognized that factors such as cigarette smoke and environmental pollution are the main drivers of the disease (1, 2), triggering a sustained inflammation state of the lungs that ultimately results in persistent cellular alterations (3, 4). Epithelial cells are particularly affected, causing a notable decline in regenerative capacity, leading to an inability to repair the damaged lung tissue (5–7). Consequently, COPD manifests as a progressive and irreversible deterioration of lung function.

In recent years, our understanding of the genetic hallmarks of COPD has improved knowledge about the functional roles of specific proteins in the disease. However, a substantial knowledge gap persists regarding the COPD epigenome, the implications/functional impact of these epigenetic alterations, and whether they are reversible. Furthermore, despite the efforts made to unravel the intricate connections between environmental factors driving the disease and defective repair mechanisms, existing therapies for COPD offer symptomatic relief and exacerbation management (8) but lack effective treatments to halt the disease progression.

In this issue of the Journal (pp. 165–177), Yeung-Luk and colleagues characterize the epigenetic alterations within the CDH1 (E-cadherin) gene (9). Their research unveiled hypermethylation patterns in COPD human samples, as well as in cells from humans and mice subjected to cigarette smoke exposure.

Previously, the authors demonstrated that alterations in E-cadherin were sufficient to drive detrimental effects observed in COPD (10). In the current study, they delved deeper into epigenetic changes affecting CDH1 and revealed both the presence of a hypermethylation status, particularly in the enhancer region D, and a reduction in TET1 demethylase gene expression. Reduced expression was accompanied by diminished RNA polymerase II activity and a depletion of H3K4M.

To address the functional role of this effect, the researchers used 5-aza-2′-deoxycytidine (5-AZA), a U.S. Food and Drug Administration–approved drug that reduces DNA methylation by forming a covalent complex with DNMT1 (DNA methyltransferase-1) at the CpG methylation sites (11). With this approach, the authors aimed to enhance E-cadherin expression and improve lung structure, potentially offering a promising avenue for COPD intervention. The authors found that barrier function integrity and cell viability in response to cigarette smoke exposure improved and was associated with a reversal of the epigenetic patterns in the CDH1 gene and with increased E-cadherin expression.

A major strength of this study lies in the attempt to characterize the functional implications of epigenome changes in COPD. Notably, the authors uncover several key elements in this intricate landscape. This can be uniquely challenging, primarily because of the limited availability of human tissue samples. Moreover, the considerable variability among individuals and even among different cells within the same individual further complicates this task. Understanding the factors underlying COPD tissue remodeling and repair has crucial implications for the future development of intervention strategies aimed at altering disease progression; thus, gaining insights into the differential epigenetic signatures may unveil critical pathways that can be exploited to restore cellular and tissue homeostasis.

Another intriguing aspect highlighted by the authors is the remarkable parallel between cigarette smoke in vitro exposure and the behavior of the cells derived from donors with COPD in terms of methylation status and E-cadherin downregulation. This observation could suggest that cigarette smoke alone may be sufficient to induce methylation changes and drive epigenetic alterations in the cells. These changes appear reversible with 5-AZA treatment, and it would be of interest to know in follow-up studies if smoking cessation is able to reverse these changes or if these are persistent.

The study used a diverse array of in vivo and ex vivo models to characterize the epigenetic changes influencing E-cadherin expression. These included patient-derived epithelial cells, mouse tracheal epithelial cells, human bronchial epithelial cells, a human epithelial cell line (16HBE), whole-lung tissue from mice, as well as precision-cut lung slices obtained from mice or human donors. It is important to note that, from an epigenetic perspective, DNA methylation is known to be tissue and even cell specific (12). In this regard, an interesting future area of research will be to characterize the epigenetic landscape at single-cell resolution, which may reveal cell-specific imprinting effects with cell-specific functional implications. A recent study identified 110 candidate regulators of disease phenotypes that were differentially methylated in COPD and linked to fibroblast repair processes (13). In light of the new findings by Yeung-Luk and colleagues, the exciting possibility that specific epigenetic pathways may drive distorted tissue repair processes in COPD emerges. Moreover, epigenetic drugs may be useful in reversing these changes. In addition, a comparative analysis involving healthy current smokers, ex-smokers, and individuals with pre-COPD could offer valuable insights into when these epigenetic imprinting effects occur in the disease process and may already be present in these groups compared with patients with late-stage COPD.

The authors also highlight the potential for pharmacological intervention with 5-AZA at low, nontoxic concentrations. This intervention resulted in an increase in E-Cadherin gene and protein expression among the different models assessed. However, a notable limitation of this intervention is its lack of specificity, as it broadly targets genome-wide methylation (14). This nonspecific action will impact other crucial genomic regions. With CRISPR technologies emerging that allow site-specific methylation changes, it could be an exciting next step to study the functional impact of individual methylation patterns. On the other hand, from a pharmacological perspective and with the knowledge at hand that multiple epigenetic changes occur in multiple cells in COPD, a broader-spectrum epigenetic drug could be a more efficacious approach. The long-term efficacy of epigenetic interventions in restoring tissue function and/or architecture remains uncertain and is a key issue to address in the future.

In summary, the manuscript by Yeung-Luk and colleagues highlights the critical need to understand how environmental insults/factors can induce alterations in the transcriptional status of the cells and/or tissues, giving rise to the onset of chronic diseases that currently lack effective treatments. Furthermore, the authors describe the protective potential effect of preventing methylation with the addition of 5-AZA by increasing E-cadherin expression in lung epithelial cells. Nevertheless, the complexity of this process remains incompletely understood, and further research is needed to ultimately define whether epigenetic reprogramming can modify COPD disease progression.