Epigenetic targets for therapeutic approaches in COPD and asthma. Nutrigenomics &ndash; possible or illusive

Oxidative stress generated by cigarette smoking, environmental pollution, or other noxious particles leads to epigenetic changes in the cells of the respiratory tract. They reflect cell adaptation in response to chronic exposure to external factors. Although there is no change in the genetic code, epigenetic changes may be heritable and translated from one generation to another, accumulating abnormalities and rendering cells into entirely different phenotype, causing disease. DNA methylation, post-translation histone modification, ubiquitination, sumoylation and miRNA transcriptional regulation are the major processes that are responsible for the epigenetic control of gene expression. All of them are reversible. They can be regulated by targeting specific enzymes/proteins involved in the process in order to mitigate inflammation. Chronic respiratory diseases have epigenetic signatures that affect gene expression in the lung. Targeting them provides the development of novel diagnostic and therapeutic approaches in respiratory medicine. Nutrigenomics reveals the beneficial effect of natural phytochemicals, affecting key steps in the signaling pathways of chronic respiratory diseases.

Download Full-text

Epigenetics

Oxford Textbook of Cancer Biology ◽

10.1093/med/9780198779452.003.0005 ◽

2019 ◽

pp. 56-70

Author(s):

Edward Hookway ◽

Nicholas Athanasou ◽

Udo Oppermann

Keyword(s):

Gene Expression ◽

Histone Deacetylases ◽

Molecular Mechanisms ◽

Current Knowledge ◽

Tumour Suppressor Genes ◽

Epigenetic Mechanisms ◽

Therapeutic Approaches ◽

Control Of Gene Expression ◽

Non Coding Rnas ◽

Epigenetic Processes

Epigenetics is a term that refers to a collection of diverse mechanisms that are important in both the control of gene expression and the transmission of this information during cell division. Epigenetic processes are deranged in many cancers, leading to a combination of inappropriate silencing of tumour suppressor genes and overexpression of oncogenes. In this chapter, the molecular mechanisms that underpin the major epigenetic processes of DNA methylation, histone modification, and non-coding RNAs will be described in both their normal physiological roles and in the context of cancer. The challenge of understanding the complexity of the interactions between different epigenetic mechanisms and the limitations of our current knowledge will be highlighted. Therapeutic approaches towards targeting deranged epigenetic processes will also be described, such as the use of small molecule inhibitors of histone deacetylases.

Download Full-text

Host-microbe cross-talk in the lung microenvironment: implications for understanding and treating chronic lung disease

European Respiratory Journal ◽

10.1183/13993003.02320-2019 ◽

2020 ◽

pp. 1902320 ◽

Cited By ~ 1

Author(s):

Reinoud Gosens ◽

Pieter S. Hiemstra ◽

Ian M. Adcock ◽

Ken R. Bracke ◽

Robert P. Dickson ◽

...

Keyword(s):

Microbial Community ◽

Cross Talk ◽

Respiratory Diseases ◽

Human Microbiome ◽

Targeted Therapeutics ◽

Foreseeable Future ◽

Prevention Strategies ◽

Therapeutic Approaches ◽

Chronic Respiratory Diseases ◽

Holistic Approaches

Chronic respiratory diseases are highly prevalent worldwide and will continue to rise in the foreseeable future. Despite intensive efforts over the recent decades, the development of novel and effective therapeutic approaches has been slow. There is however new and increasing evidence that communities of microorganisms in our body, the human microbiome, are crucially involved in the development and progression of chronic respiratory diseases. Understanding the detailed mechanisms underlying this cross-talk between host and microbiota is critical for development of microbiome- or host-targeted therapeutics and prevention strategies. Here we review and discuss the most recent knowledge on the continuous reciprocal interaction between the host and microbes in health and respiratory disease. Furthermore, we highlight promising developments in microbiome-based therapies and discuss the need to employ more holistic approaches of restoring both the pulmonary niche and the microbial community.

Download Full-text

Epigenetics – relevance to drug safety science

Toxicology Research ◽

10.1039/c2tx00003b ◽

2012 ◽

Vol 1 (1) ◽

pp. 23-31 ◽

Cited By ~ 11

Author(s):

Catherine C. Priestley ◽

Mark Anderton ◽

Ann T. Doherty ◽

Paul Duffy ◽

Howard R. Mellor ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Drug Safety ◽

Tumour Progression ◽

Evaluation Studies ◽

Stem Cell Differentiation ◽

Specific Gene ◽

Epigenetic Changes ◽

Genotoxic Carcinogens ◽

Epigenetic Signatures

Abstract Epigenetics describes the study of heritable changes in gene expression that occur in the absence of a change to the DNA sequence. Specific patterns of epigenetic signatures can be stably transmitted through mitosis and cell division and form the molecular basis for developmental stage- and cell type-specific gene expression. Associations have been observed that endogenous and exogenous stimuli can change the epigenetic control of both somatic and stem cell differentiation and thus influence phenotypic behaviours and/or disease progression. In relation to drug safety, DNA methylation changes have been identified in many stages of tumour development following exposure to non-genotoxic carcinogens. However, it is not clear whether DNA methylation changes cause cancer, or arise as a consequence of the transformed state. Toxic agents could act at different levels, by directly modifying the epigenome or indirectly by altering signalling pathways. These alterations in chromatin structure may or may not be heritable but are probably reversible. That said, there is currently insufficient data to support inclusion of epigenetic profiling into pre-clinical evaluation studies. Several international collaborations aim to generate data to determine whether epigenetic modifications are causal links in disease and/or tumour progression. It will only be when an understanding of chemical mode-of-action is required that evaluation of epigenetic changes might be considered. The current toxicological testing battery is expected to identify any potential adverse effects regardless of the mechanism, epigenetic or otherwise. It is recommended that toxicologists keep a close watch of new developments in this field, in particular identification of early epigenetic markers for non-genotoxic carcinogenicity. Scientific collaborations between academia and industry will help to understand inter-individual variations in response to drug and toxin exposure to be able to distinguish between adverse and non-adverse epigenetic changes.

Download Full-text

Epigenetics of obesity

CARDIOVASCULAR THERAPY AND PREVENTION ◽

10.15829/1728-8800-2020-2632 ◽

2020 ◽

Vol 19 (6) ◽

pp. 2632

Author(s):

O. M. Drapkina ◽

O. T. Kim

Keyword(s):

Gene Expression ◽

Deoxyribonucleic Acid ◽

Fat Distribution ◽

Epigenetic Modifications ◽

Lifestyle Changes ◽

Epigenetic Mechanisms ◽

Epigenetic Changes ◽

Critical Periods ◽

Affect Gene Expression

The pathophysiology of obesity is complex and includes changes in eating behavior, genetic, epigenetic, environmental factors, and much more. To date, ~40 genetic polymorphisms are associated with obesity and fat distribution. However, since these options do not fully explain the inheritance of obesity, other options, such as epigenetic changes, need to be considered. Epigenetic modifications affect gene expression without changing the deoxyribonucleic acid sequence. In addition, environmental exposure during critical periods of development can affect the epigenetic tags and lead to obesity. A deeper understanding of the epigenetic mechanisms underlying obesity can aid in prevention based on lifestyle changes. This review focuses on the role of epigenetic modifications in the development of obesity and related conditions.

Download Full-text

Oncometabolite D-2-Hydroxyglutarate enhances gene silencing through inhibition of specific H3K36 histone demethylases

eLife ◽

10.7554/elife.22451 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 13

Author(s):

Ryan Janke ◽

Anthony T Iavarone ◽

Jasper Rine

Keyword(s):

Gene Expression ◽

Saccharomyces Cerevisiae ◽

Gene Silencing ◽

Dna Demethylation ◽

Epigenetic Changes ◽

Central Metabolism ◽

Histone Demethylases ◽

Altered Gene Expression ◽

Altered Gene ◽

Affect Gene Expression

Certain mutations affecting central metabolism cause accumulation of the oncometabolite D-2-hydroxyglutarate which promotes progression of certain tumors. High levels of D-2-hydroxyglutarate inhibit the TET family of DNA demethylases and Jumonji family of histone demethylases and cause epigenetic changes that lead to altered gene expression. The link between inhibition of DNA demethylation and changes in expression is strong in some cancers, but not in others. To determine whether D-2-hydroxyglutarate can affect gene expression through inhibiting histone demethylases, orthologous mutations to those known to cause accumulation of D-2-hydroxyglutarate in tumors were generated in Saccharomyces cerevisiae, which has histone demethylases but not DNA methylases or demethylases. Accumulation of D-2-hydroxyglutarate caused inhibition of several histone demethylases. Inhibition of two of the demethylases that act specifically on histone H3K36me2,3 led to enhanced gene silencing. These observations pinpointed a new mechanism by which this oncometabolite can alter gene expression, perhaps repressing critical inhibitors of proliferation.

Download Full-text