Epigenetics. 2.2.4 Gene regulation 2.2.5 Genomics 2.2.6 Metagenomics 2.2.7 Transcriptomics 2.2.8 Proteomics
Epigenetics. Xxxxxx Xxxxxxxxxx originally coined the term 'epigenetics' in 19421 to describe the processes mediating 'epigenesis', the theory dating from Aristotle that organisms develop progressively by differentiation rather than 'preformationism',2 the once commonly-held view that organisms develop from miniature versions of the adult form. Waddington had little idea of the molecular mechanisms behind development, with the fundamental demonstration that DNA was the genetic material not coming until 1944 3. Yet, chromosomes had been identified in 1879 by Xxxxxxx Xxxxxxx, and following his seminal studies in Drosophila, Xxxxxx Xxxx Xxxxxx in 1911 mapped specific genes to the X-chromosome. Indeed, some of the first hints that genetics alone were insufficient to account for phenotype came from so called 'eversporting' translocation mutations in Drosophila, where preservation of all chromosomal material, but in different rearrangements, resulted in distinct phenotypes, an epigenetic phenomenon now referred to as position effect variegation where neighboring chromatin spreads to silence or activate nearby genes. Yet even with limited mechanistic knowledge, Waddington's theory of an 'epigenetic landscape', essentially that as cells develop they acquire distinct epigenetic states, has become dogma in biology. We know now that this epigenetic state encompasses an array of mitotically heritable molecular modifications to chromatin, most prominently DNA methylation and histone modifications and variants. It is clear that programmed epigenetic changes during development result in the expression of distinct gene sets that underlie the morphological and phenotypic changes to cells embryologists have long studied. Furthermore, we know now that aberrant epigenetic changes play a crucial role in human disease, especially in oncogenesis and cancer progression. DNA Methylation & CpG Islands One of the earliest examples of a clear role for epigenetics in gene regulation comes from X-chromosome inactivation. In female placental mammals, it was demonstrated at least at early as the 1950s that one X-chromosome is randomly epigenetically silenced early in development4,5 and in 1975 it was proposed that DNA methylation mediated this silencing6,7, a fact confirmed by dozens of studies since8. Indeed, DNA methylation is now perhaps the best- studied chromatin xxxx, with essential roles in development, gene silencing, aging, and carcinogenesis. DNA methylation occurs at the 5-carbon of cytosin...
Epigenetics. The study of heritable changes in gene function that occur without a change in the sequence of nuclear DNA and the processes involved in the unfolding development of an organism. Epigenetic age: An estimate of biological age based on changes in epigenetic marks at particular locations along the genome. Epigenetic drift: Divergence of the epigenome as a function of age due to stochastic changes in epigenetic marks. Epigenetic marks: Features not directly governed by the genetic code, which include methylation of DNA and covalent modification of histone proteins. The latter may be tagged with methyl, acetyl, ubiquitin, phosphate, poly(ADP)ribose and other biochemical groups. These groups and their particular pattern of protein modification (e.g. mono-, bi-, tri-methylated at different amino acids and combinations of amino acids) modify the function of the tagged proteins and influence the way genes are expressed. Epigenome: The comprehensive collection of genome-wide epigenetic phenomena, including DNA-methylation patterns, chromatin modifications, and non-coding RNA. Epigenomic reprogramming: Resetting epigenetic marks so they resemble those of other cells from earlier developmental stages. This is of particular relevance for germline cells after the fusion of gametes when the genome is brought back into a "zero-state" of gene expression. Epithelium: The tissue covering the outer surface of the body, the mucous membranes and cavities of the body.
Epigenetics. Epigenetics, broadly speaking, is the study of gene expression or cellular phenotype that occurs without changes to the DNA sequence itself. While in classical genetics phenotypic changes require genetic alterations, epigenetics fills the gap as “the bridge between genotype and phenotype” (Xxxxxxxx et al., 2007). A major molecular mechanism and well characterized example of epigenetics is DNA methylation, the enzymatic addition of a methyl group to DNA performed by DNA methyltransferases (DNMT) on the 5’-carbon of the pyrimidine ring in cytosine (Xxxxxx and Xxxxx, 2013). DNA methylation can perform a range of functions within a cell depending on the cellular context (Xxxxx, 2013). Traditionally, DNA methylation was viewed as an important factor in gene expression repression, possibly by blocking transcription from promoters by preventing the binding of transcription factors. Currently, DNA methylation proves to be more complex than a mere expression repressor and it is crucial for cell differentiation and development (Xxxxxxxx, 2008). For instance, promoter methylation can stabilize gene repression in imprinted genes (Xxxxx, 2013), while the methylation of a gene body may positively correlate with active transcription (Xxxxxxx, 2007). In undifferentiated cells, DNA methylation maintains the cell pluripotency, while later in development DNA methylation is involved in maintaining the differentiation state, and different cell lineages exhibit different DNA methylation patterns (Xxxxxxx et al., 2010; Roost et al., 2017). It is also observed that during regular cell replication and quiescence, DNA methylation is stable in human primary fibroblasts (Vandiver et al., 2015). Although DNA methylation can be considered stable in different cell types, it is not a static feature. In fact, there appears to be a rapid turnover of DNA methylation in human cells, which also complicates how a certain epigenetic event trigger actually induces changes in DNA methylation levels (Xxxxxxxx et al., 2012).
Epigenetics. Its potential impact on the history of coronary artery disease In McKeown’s work we see arguments for evidence that a disease and its mortality could have been impacted by another cataclysmic event as just discussed in terms of the 1918 Influenza epidemic. We also see reference to the possible role that epigenetics might have played. In this section, I would like to address the theoretical role of epigenetics in the course of disease evolution, specifically coronary artery disease, and its potential impact for altering mortality. The term epigenetics, which taken literally means “above genetics,” was first coined by developmental biologist Conrad Waddington in 1939. He used the term to describe “the causal interactions between genes and their products, which bring the phenotype into being.” Subsequent to the discovery of the structure of DNA by James Watson and Francis Crick in the 1950s, epigenetics was “defined as those heritable changes in gene expression that are not due to any alteration in DNA sequence.”83 As we have learned in the years since both the coining of the term epigenetics and the elucidation of the material that makes up the genome, it is quite clearly not just the DNA that determines phenotype. All cells of an organism contain the same DNA coded genetic material but nonetheless manifest both morphological and functional differences. It is clear that the field of genetics alone cannot explain all human variation and 82 Maria Inês Azambuja and Bruce B. Duncan. “Influenza and Coronary Heart Disease.” 564. 83 Manuel Esteller. “An Introduction to Epigenetics.” In Manuel Esteller, ed. Epigenetics in Biology and Medicine. Boca Raton: CRC Press (2009): 1.
