Abstract
Asthma is the most common non-communicable chronic disease of childhood. Despite its high prevalence, to date we lack methods that are both efficient and accurate in diagnosing asthma. Most traditional approaches have been based on garnering clinical evidence, such as risk factors and exposures. Given the high heritability of asthma, more recent approaches have looked at genetic polymorphisms as potential “risk factors.” However, genetic variants explain only a small proportion of asthma risk, and have been less than optimal at predicting risk for individual subjects. Epigenomic studies offer significant advantages over previous approaches. Epigenetic regulation is highly tissue-specific, and can induce both short- and long-term changes in gene expression. Such changes can start in utero, can vary throughout the life span, and in some instances can be passed on from one generation to another. Most importantly, the epigenome can be modified by environmental factors and exposures, and thus epigenetic and transcriptomic profiling may yield the most accurate risk estimates for a given patient by incorporating environmental (and treatment) effects throughout the lifespan. Here we will review the most recent advances in the use of epigenetic and transcriptomic analysis for the early diagnosis of asthma and atopy, as well as challenges and future directions in the field as it moves forward. We will particularly focus on DNA methylation, the most studied mechanism of epigenetic regulation.
Highlights
Specialty section: This article was submitted to Pediatric Pulmonology, a section of the journal Frontiers in Pediatrics
Epigenetic regulation and gene expression are responsive to environmental factors, and could bridge the gap between an individual’s genetic predisposition and the environment to which they are exposed—whether this is in utero, in early life, or later on
The study evaluated whole-blood DNA methylation later in childhood and found 179 CpG sites significantly associated with asthma (FDR P < 0.05), none of which overlapped with the nine markers that were significant in the newborn blood analysis
Summary
The term “epigenetics” encompasses the regulation of cell activity and gene expression by mechanisms that do not alter the genetic code (DNA sequence) itself. Methyl groups (CH3) are added to cytosine bases, resulting in 5-methylcytosine residues These physically protrude into and obstruct the major groove of the DNA helix, while indirectly facilitating histone deacetylation. While CpG sites exist throughout the genome, they occur with much higher frequency in areas denominated CpG islands, which are often located near the promoter regions of genes Higher methylation in these islands makes it more difficult for transcription factors to assemble, further down-regulating expression of the corresponding genes. The end-result of DNA methylation is often marked downregulation of gene expression Beyond this down-regulation of gene expression, DNA methylation outside of gene promoters may have functional consequences that are poorly understood; DNA methylation may less frequently, occur at non-CpG sites. Most human studies of the epigenomics of asthma have focused on CpG DNA methylation and gene expression
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