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. 1. Introduction 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” [1, 2]. In simpler terms, epigenetics is the study of changes in the function of genes that do not involve changes in the DNA sequence. It is the study of how the same sequence of DNA can produce significantly different phenotypes as a result of differing biochemical changes that alter gene availability for protein production [1, 3]. What makes this even more fascinating than a nature versus nurture discussion is that there are a small number of known genes in which specific biochemical modifications can impact the phenotype of offspring and are thus inheritable yet do not alter base pair sequencing of DNA. This is termed DNA imprinting [3]. A classic example of this is seen on chromosome 15 in Angelman and Prader-Willi syndromes where DNA methylation is involved in genomic imprinting of parental germ line cells, impacting the phenotype of the offspring depending upon whether the affected chromosome is paternal or maternal in
References
[1]
A. D. Goldberg, C. D. Allis, and E. Bernstein, “Epigenetics: a landscape takes shape,” Cell, vol. 128, no. 4, pp. 635–638, 2007.
[2]
C. H. Waddington, “The epigenotype,” Endeavour, vol. 1, pp. 18–20, 1942.
[3]
W.-Y. Tang and S.-M. Ho, “Epigenetic reprogramming and imprinting in origins of disease,” Reviews in Endocrine and Metabolic Disorders, vol. 8, no. 2, pp. 173–182, 2007.
[4]
A. I. Dagli and C. A. Williams, “Angelman syndrome,” in GeneReviews, R. A. Pagon, T. D. Bird, and C. R. Dolan, Eds., University of Washington, Seatle, Wash, USA, 2011.
[5]
A. Reis, B. Dittrich, I. V. Greger et al., “Imprinting mutations suggested by abnormal DNA methylation patterns in familial Angelman and Prader-Willi syndromes,” American Journal of Human Genetics, vol. 54, no. 5, pp. 741–747, 1994.
[6]
D. J. Driscoll, J. L. Miller, and S. Schwartz, “Prader-Willi syndrome,” in GeneReviews, R. A. Pagon, T. D. Bird, and C. R. Dolan, Eds., University of Washington, Seatle, Wash, USA, 2012.
[7]
W. F. Carson IV, K. A. Cavassani, Y. Dou, and S. L. Kunkel, “Epigenetic regulation of immune cell functions during post-septic immunosuppression,” Epigenetics, vol. 6, no. 3, pp. 273–283, 2011.
[8]
L. B. Jorde, “Genes and genetic diseases,” in Pathophysiology: The Biological Basis for Disease in Adults and Children, K. L. McCance and S. E. Huether, Eds., pp. 126–163, Mosby Elsevier, Toronto, Canada, 6th edition, 2010.
[9]
T. T. Cornell, J. Wynn, T. P. Shanley, D. S. Wheeler, and H. R. Wong, “Mechanisms and regulation of the gene-expression response to sepsis,” Pediatrics, vol. 125, no. 6, pp. 1248–1258, 2010.
[10]
National Human Genome Research Institute, “The national human genome research institute (NHGRI) fact sheet: epigenetics,” June 2013, http://www.genome.gov/multimedia/illustrations/FactSheet_EpigenomicMechanisms.pdf.
[11]
S. W. Kang, P.-A. B. Shih, R. O. Mathew et al., “Renal kallikrein excretion and epigenetics in human acute kidney injury: expression, mechanisms and consequences,” BMC Nephrology, vol. 12, no. 1, article 27, 2011.
[12]
M. F. Mehler, “Epigenetic principles and mechanisms underlying nervous system functions in health and disease,” Progress in Neurobiology, vol. 86, no. 4, pp. 305–341, 2008.
[13]
S. K. Madathil, P. T. Nelson, K. E. Saatman, and B. R. Wilfred, “MicroRNAs in CNS injury: potential roles and therapeutic implications,” BioEssays, vol. 33, no. 1, pp. 21–26, 2011.
[14]
N.-K. Liu and X.-M. Xu, “MicroRNA in central nervous system trauma and degenerative disorders,” Physiological Genomics, vol. 43, no. 10, pp. 571–580, 2011.
[15]
T. Zhou, J. G. N. Garcia, and W. Zhang, “Integrating microRNAs into a system biology approach to acute lung injury,” Translational Research, vol. 157, no. 4, pp. 180–190, 2011.
[16]
H. S. Warren, C. M. Elson, D. L. Hayden et al., “A genomic score prognostic of outcome in trauma patients,” Molecular Medicine, vol. 15, no. 7-8, pp. 220–227, 2009.
[17]
W. A. Knaus, D. P. Wagner, E. A. Draper et al., “The APACHE III prognostic system. Risk prediction of hospital mortality for critically ill hospitalized adults,” Chest, vol. 100, no. 6, pp. 1619–1636, 1991.
[18]
W. A. Knaus, J. E. Zimmerman, D. P. Wagner, E. A. Draper, and D. E. Lawrence, “APACHE-acute physiology and chronic health evaluation: a physiologically based classification system,” Critical Care Medicine, vol. 9, no. 8, pp. 591–597, 1981.
[19]
A. G. Cuenca, L. F. Gentile, M. C. Lopez, et al., “Development of a genomic metric that can be rapidly used to predict clinical outcome in severely injured trauma patients,” Critical Care Medicine, vol. 41, no. 5, pp. 1175–1185, 2013.
[20]
E. V. Geiger, M. Maier, S. Schiessling, et al., “Subsequent gene expression pattern in dendritic cells following multiple trauma,” Langenbeck's Archives of Surgery, vol. 398, no. 2, pp. 327–333, 2013.
