Epigenetics is the study of alterations in the function of genes that do not involve changes in the DNA sequence. Within the critical care literature, it is a relatively new and exciting avenue of research in describing pathology, clinical course, and developing targeted therapies to improve outcomes. In this paper, we highlight current research relative to critical care that is focused within the major epigenetic mechanisms of DNA methylation, histone modification, microRNA regulation, and composite epigenetic scoring. Within this emerging body of research it is quite clear that the novel therapies of the future will require clinicians to understand and navigate an even more complex and multivariate relationship between genetic, epigenetic, and biochemical mechanisms in conjunction with clinical presentation and course in order to significantly improve outcomes within the acute and critically ill population.
Critical care practice is beginning to look toward more specific cellular, biochemical, and genetic interventions in order to make a significant impact on patient outcomes. In addition to the extensive cellular, biochemical, and genetic body of research in process today, the science of epigenetics has become a more frequent focus within the critical care literature over the past 5+ years.
Though epigenetics may appear to be relatively new to us in the critical care discipline, it has actually been studied for over 70 years and was first described by Conrad Waddington in 1942 as “the branch of biology which studies the casual interactions between genes and their products, which bring the phenotype into being” [
Of even more importance to critical care, epigenetic changes of somatic cells can be propagated to progeny of those cells within an individual, impacting phenotypic expression during the course of critical illness. For example, epigenetic changes altering the effectiveness of immune cells to respond to pathogens could persist in new immune cells which inherited the epigenetic changes. These prior epigenetic changes could thus have a direct effect on an individual’s ability to respond to sepsis in the future.
Interest in critical care has focused on DNA methylation, histone modification, and microRNA (miRNA). These epigenetic mechanisms can result in increased or decreased gene products. Decreased gene expression may result from downregulation of genes (the transcription of RNA from specific gene sequences is inhibited or arrested). Increased gene expression may result from upregulation of genes (increased transcription of RNA from targeted genes). However, for genes which provide a messenger RNA (mRNA) template for protein production, additional factors can influence the amount of protein produced from mRNA; for example, how often each mRNA is used for transcription and how quickly the mRNA is degraded can influence the amount of protein produced. More specifically, DNA methylation (as the result of enzymes known as DNA methylases) is the attachment of methyl groups (CH3) to cytosine bases within a DNA sequence; demethylation is removal of these methyl groups. As the quantity and pattern of DNA methylation increases, gene transcription into messenger RNA (mRNA) decreases; demethylation can increase gene transcription. Thus, DNA methylation represses expression of the affected genes. Methylation patterns in DNA can be transmitted to daughter cells during mitosis or transmitted to offspring as a result of meiosis [
Furthermore, since DNA is an extremely long molecule, it must be coiled and folded in order to fit into a nucleus (Figure
Epigenetics marks (courtesy: National Human Genome Research Institute) [
Epigenetic regulation can also occur through microRNAs (miRNAs). These small noncoding RNAs can act as regulatory elements in both transcription and translation. Noncoding RNAs are also involved in modifying phenotype through various mechanisms, such as posttranscriptional and transcriptional interference pathways, in which they may alter chromatin and/or DNA methylation processes to further stabilize gene silencing [
The extent of DNA methylation, histone modification, and microRNA activity may impact the function of genes without any alterations in the DNA sequence. These epigenetic mechanisms can have direct phenotypic implications. Several intriguing examples have recently been highlighted in critical care and are discussed below.
When gene expression is altered, the potential for significant phenotypical alterations to pathology, disease progression, and short- and long-term outcomes exists. Within critical care, research regarding the influence of genetics is in its early stages, and investigators are just beginning to look toward the science of epigenetics for explanations for patient and population differences in susceptibility to illness, clinical course, and outcomes. In the following sections, specific examples of epigenetic research focused on critical illness are provided.
Epigenetic regulation, in which gene expression is altered and may significantly impact critical illness outcomes, can occur through direct methylation of DNA cytosine bases resulting in downregulation of genes. Alternatively, demethylation might upregulate expression of genes. An example of downregulation through methylation in acute illness has been associated with the pathological processes associated with acute kidney injury (AKI) [
AKI is a common complication in critical care patients, with an incidence greater than 5–10%, contributing to an increase in morbidity and mortality. Previous animal studies have suggested that altered expression of the KLK1 gene, which results in the transcription/translation of the serine protease kallikrein, may be related to AKI. Kallikrein is involved in the biochemical reaction in the kidney to produce kallidin, which pharmaceutically appears to have vasodilator and natriuretic properties in animals. Additionally, increased concentrations of kallikrein have been shown to be protective in animals, diminishing renal cell death by apoptosis and inflammation [
Kang and colleagues [
Two significant contributions to the state of epigenetic science in acute illness can be derived from the work of Kang et al. [
Another type of epigenetic mechanism, histone acetylation, is now a potential therapeutic target in critical illness. As previously discussed, DNA is more or less accessible for transcription depending upon how it is wound around histones in the nucleus. Acetylation of histones occurs when acetyl groups are added to specific amino acids (lysines) comprising the histones. Acetylation of histones changes the availability of the DNA in that area to transcription. Inhibitors of histone acetylation have been examined in animal models of hemorrhagic shock and LPS-induced sepsis; inhibiting histone acetylation reduces immune responsiveness during the acute episode, and has been associated with better outcomes [
Although histone modifiers are currently being explored as therapeutic agents, there is additional reason for caution because of emerging evidence about the sequella of histone modifications on immunity following sepsis. Patients who survive sepsis have profound and long lasting immunosuppression which can impede appropriate response to pathogens; 5- and 8-year survival is shorter compared to age-matched people who have not had severe sepsis. Evidence is accumulating that this consequence of critical illness is associated with epigenetic changes in immune cells. In a recent review of epigenetic mechanisms after sepsis, Carson IV and colleagues [
MiRNA is highly expressed in central nervous system tissues, and research suggests that they play a role in neurodevelopment and neural plasticity [
MiRNAs contribute to differentiation and regulation of the immune system and have been implicated in chronic pulmonary diseases with an inflammatory component, including asthma, chronic obstructive pulmonary disease, and cystic fibrosis [
Better understanding of the positive and negative effects of miRNAs on the course of critical illness would be beneficial in at least two ways. First, it would help to elucidate mechanisms underlying pathogenesis and protective response; this could identify potential targets for pharmacotherapeutic or nonpharmacotherapeutic interventions. Second, in the future miRNAs could themselves be targets for intervention, with a goal of enhancing regulatory effects related to protective responses and suppressing regulatory effects associated with pathogenesis.
Warren and colleagues [
A second group of investigators [
Interestingly, temporal gene expression patterns in dendritic cells of 10 patients over the first four days following trauma identified upregulation of genes involved in antigen presentation [
Stratification by genetic risk profile could inform when to initiate targeted therapy, who is most likely to benefit, and whether patients are responding to prescribed therapies. This information will be most useful if it can be assessed early in the course of critical illness. However, the specific epigenetic mechanisms underlying the changes in gene expression were not elucidated in the above studies [
The state of the science in understanding the role of epigenetic regulation as it relates to the pathology of critical illness, clinical course, and outcomes is evolving rapidly yet still well within its infancy. Available research exists primarily within the lab, animal, and preclinical realm and thus has yet to be translated to the direct care of the critically ill person. Epigenetic tools and methodologies continue to evolve and improve, bringing the possibility of real time data to the point of care for therapeutic intervention closer to reality. Better identification and understanding of the role of epigenetic modifications that are associated with the complex regulatory and disregulatory processes of the disease state is essential and it is apparent that our approach to therapeutically target epigenetic modifications to improve outcomes may only be a single component of even more complex novel therapies to come.
The authors do not have any conflict of interests with the content of the paper.