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Epigenetic and Metabolic Alterations in Cancer Cells: Mechanisms and Therapeutic Approaches
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
Deregulation of cellular energetics is a major hallmark of carcinogenesis. In recent years, many studies have unraveled novel roles of metabolites in directly modulating epigenetic enzymes. In a majority of cases, a deregulated metabolic profile modulates epigenome by either (1) altering levels of substrates, cofactors or inhibitors that are required for optimal function of epigenetic modification enzymes; or (2) generating novel oncometabolites that affects the activity of these enzymes. Reciprocally, epigenetic dysfunction has an equally important contribution to tumor metabolism by (1) epigenetic regulation of the expression of metabolic enzymes; or (2) modulating oncogenic signaling pathways such as c-Myc or HIF, which in turn, mediate the expression of numerous metabolic enzymes or pathways. Interplay between epigenetics and metabolism might constitute a positive vicious cycle to promote tumorigenesis.
“Omics”
Published in Kirk A. Phillips, Dirk P. Yamamoto, LeeAnn Racz, Total Exposure Health, 2020
The epigenome broadly refers to molecular marks and mechanisms that control the structural organization of the genome and thus exert an influence on gene expression without changing the actual coding sequence (Rivera and Ren 2013). Epigenetic changes can act as an on/off switch to activate/inactivate large genomic areas (an example being X-chromosome inactivation) or as a “rheostat” finely tuning gene expression. The deposition of epigenetic marks (and thus gene expression levels) is a mechanism by which cell and tissue types are determined. Epigenetic control is achieved most commonly by modifications of DNA or histones or through regulatory RNA. Common epigenetic marks include methylation/demethylation at cytosine residues of cytosine-guanosine dinucleotides (CpG) or histone tails (which can also be modified by acetylation/deacetylation). The modifications at histones modulate chromatin structure and accessibility of transcription factors, while cytosine methylation/hydroxymethylation generally leads to gene silencing through recruitment of repressors like methyl-binding protein domain protein and histone deacetylases. CpG dinucleotides are overrepresented in promoters and regulatory regions and some repetitive DNA elements.
Bathtub Curves for Humans and Components
Published in Franklin R. Nash, Reliability Assessments, 2017
Epigenetics is the set of modifications to the genetic material that changes the ways genes are switched on or off, but which do not alter the genes themselves [35]. Barring the effects of radiation, for example, the basic structure of the genome (DNA) remains unchanged during the life of an organism. The nongenetic chemicals (software), known as epigenomes or epigenetic tags, can orchestrate the development of an organism and act as chemical switches that activate (turn-on) or deactivate (turn-off) genes at various times and locations on the DNA (hardware). The epigenomes are preserved during cell division and some are inheritable, so inheritance does not occur exclusively through the DNA code passing from parent to offspring.
Posthumanism: Creation of ‘New Men’ Through Technological Innovation
Published in The New Bioethics, 2021
The expression and activity of genes depends not only the genetic code in the genome, but also on the microstructure (not the code) of the DNA itself and the proteins associated with its packaging in the chromosome; the chemical state of this microstructure and associated proteins constitutes the epigenome. Epigenetics is ‘the study of the mechanisms of temporal and spatial control of gene activity during the development of complex organisms’ (Holliday 1990, 329). Changes in the epigenome can be passed on the offspring via transgenerational epigenetic inheritance (Bernstein et al. 2007). Epigenetic changes wrought by one’s diet, behaviour, or surroundings can work their way into the germ line and echo far into the future (Morgan and Whitelaw 2008). Thus, changes in the phenotype include mechanisms that do not involve alterations of the DNA sequence; consequently, traits depend both on the genome and the epigenome, and modifications of the former alone may not result in the desired traits.
Transhumanist Genetic Enhancement: Creation of a ‘New Man’ Through Technological Innovation
Published in The New Bioethics, 2021
The approximately 25,000 genes identified in the human genome are widely regarded as the instruction book for the human body. But genes themselves need instructions for what to do, and where and when to do it. Those instructions are not always found in the nucleotides of the DNA itself but frequently on an array of chemical markers and switches, known collectively as the epigenome, that lie along the length of the DNA double helix; epigenetic switches and markers help switch on or off the expression of particular genes. The epigenome could be regarded as a complex software code capable of inducing the DNA hardware to manufacture an enormous variety of proteins, cell types, and individuals. The epigenome is just as critical as DNA to the healthy development of humans and is sensitive to cues from the environment that can affect the body and brain of individuals throughout their lives (Watters 2006).
Regulation of cytochrome P450 expression by microRNAs and long noncoding RNAs: Epigenetic mechanisms in environmental toxicology and carcinogenesis
Published in Journal of Environmental Science and Health, Part C, 2019
Dongying Li, William H. Tolleson, Dianke Yu, Si Chen, Lei Guo, Wenming Xiao, Weida Tong, Baitang Ning
Various environmental factors are known to influence the expression of miRNAs.69 Modifications in the epigenome due to environmental exposure can have trans-generational effects, i.e. phenotypes or disease states caused by epigenetic alteration from individuals exposed to toxicants can be inherited by their offspring in multiple generations.70 Numerous environmental stressors from various sources, including tobacco, alcohol, food, air pollution, pharmaceuticals, and medical and commercial products, have been shown to alter the expression of miRNAs and lncRNAs.71,72 For example, cigarette smoke can cause dysregulation of many miRNA species, extensive changes in protein expression, and overexpression of a cancer-related lncRNA, SCAL1, in the lung.73,74 BaP treatment downregulates miR-320 and miR-506 but upregulates miR-22, miR-106b, miR-494, miR-638 and lncRNA-DQ786227, which are associated with cancerous transformation of bronchial epithelial cells upon BaP exposure.72 Inorganic arsenic, which may be found in contaminated food and drinking water, induces overexpression of KRAS and RAS oncogenes by inhibiting the expression of multiple oncogene-targeting miRNAs including let-7, miR-134, miR-138, miR-155, miR-181d, miR-205, and miR-373.75 We refer readers to excellent reviews by Marrone et al.72 and Yu and Cho71 for more information on chemically-induced miRNA responses. While the observation of miRNA dysregulation due to environmental exposure is extensively reported, the mechanisms underlying how environmental chemicals alter miRNA expression are less studied. Izzotti and Pulliero have summarized several published mechanisms, including the interconnection of p53 with the miRNA processing machinery affecting miRNA processing in the nucleus, miRNA adduct formation blocking DICER’s access to precursor miRNAs, and the binding between xenobiotic metabolites and DICER inhibiting miRNA maturation.76 It is also possible that xenobiotics may activate transcription factors that regulate the expression of miRNA encoding genes.