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Cigarette smoking and DNA methylation.

Lee KW, Pausova Z - Front Genet (2013)

Bottom Line: DNA methylation is a quantitative trait determined by a complex interplay of genetic and environmental factors.Genetic variants at a specific locus can influence both regional and distant DNA methylation.Epigenome-wide association studies have uncovered candidate genes associated with cigarette smoking that have biologically relevant functions in the etiology of smoking-related diseases.

View Article: PubMed Central - PubMed

Affiliation: Physiology and Experimental Medicine, The Hospital for Sick Children, University of Toronto Toronto, ON, Canada.

ABSTRACT
DNA methylation is the most studied epigenetic modification, capable of controlling gene expression in the contexts of normal traits or diseases. It is highly dynamic during early embryogenesis and remains relatively stable throughout life, and such patterns are intricately related to human development. DNA methylation is a quantitative trait determined by a complex interplay of genetic and environmental factors. Genetic variants at a specific locus can influence both regional and distant DNA methylation. The environment can have varying effects on DNA methylation depending on when the exposure occurs, such as during prenatal life or during adulthood. In particular, cigarette smoking in the context of both current smoking and prenatal exposure is a strong modifier of DNA methylation. Epigenome-wide association studies have uncovered candidate genes associated with cigarette smoking that have biologically relevant functions in the etiology of smoking-related diseases. As such, DNA methylation is a potential mechanistic link between current smoking and cancer, as well as prenatal cigarette-smoke exposure and the development of adult chronic diseases.

No MeSH data available.


Related in: MedlinePlus

Effects of cigarette smoke exposure on DNA methylation. Cigarette smoke has been shown to modulate DNA methyltransferase 1 (DNMT1) content, both at the transcript and protein level, and enzymatic activity separately in different cell types. Double-stranded DNA breaks may be induced by cigarette smoke, which subsequently recruits DNMT1 adjacent to the repair site. DNA-binding proteins, such as Sp1, are activated by cigarette smoke and protect CpG sites from de novo methylation. In the context of prenatal exposure, cigarette smoke induces hypoxia in the embryo, which in turn modulates methyl group availability.
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Figure 2: Effects of cigarette smoke exposure on DNA methylation. Cigarette smoke has been shown to modulate DNA methyltransferase 1 (DNMT1) content, both at the transcript and protein level, and enzymatic activity separately in different cell types. Double-stranded DNA breaks may be induced by cigarette smoke, which subsequently recruits DNMT1 adjacent to the repair site. DNA-binding proteins, such as Sp1, are activated by cigarette smoke and protect CpG sites from de novo methylation. In the context of prenatal exposure, cigarette smoke induces hypoxia in the embryo, which in turn modulates methyl group availability.

Mentions: Cigarette smoke is considered one of the most powerful environmental modifiers of DNA methylation (Breitling et al., 2011). The specific mechanisms of how cigarette smoke may alter DNA methylation are becoming better understood (Figure 2). First, cigarette smoke may modulate it through DNA damage and subsequent recruitment of DNMTs. Carcinogens in cigarette smoke, such as arsenic, chromium, formaldehyde, polycyclic aromatic hydrocarbons, and nitrosamines (Smith and Hansch, 2000; Suter et al., 2010), can damage DNA by causing double-stranded breaks, as shown in mouse embryonic stem cells exposed to cigarette-smoke condensate (Huang et al., 2012). In these experiments, survivor cells display a high capacity for DNA repair and normal karyotypes (Huang et al., 2012). The DNA repair sites recruit DNMT1 (Mortusewicz et al., 2005), which methylates CpGs adjacent to the repaired nucleotides (Cuozzo et al., 2007). Second, cigarette smoke may also modulate DNA methylation through nicotine effects on gene expression (Lee and D’Alonzo, 1993). Nicotine binds to and activates the nicotinic acetylcholine receptors (present abundantly in the central and peripheral nervous systems) and thus increases intracellular calcium and leads to downstream activation of cAMP response element-binding protein, a key transcription factor for many genes (Shen and Yakel, 2009). Acting possibly through this pathway, nicotine has been shown to downregulate DNMT1 mRNA and protein expression in mouse brain neurons (Satta et al., 2008). Third, cigarette smoke may alter DNA methylation indirectly through the modulation of expression and activity of DNA-binding factors. It has been demonstrated, for example, that cigarette-smoke condensate increases Sp1 expression and binding to DNA in lung epithelial cells (Mercer et al., 2009; Di et al., 2012). Sp1 is a common transcription factor that binds to GC-rich motifs in gene promoters (Kadonaga et al., 1987) and plays a key role in early development; as such, it may prevent de novo methylation of CpGs within these motifs during early embryogenesis (Han et al., 2001). Fourth, cigarette smoke may alter DNA methylation via hypoxia – cigarette smoke contains carbon monoxide that binds to hemoglobin (competitively with oxygen) and thus decreases tissue oxygenation (Olson, 1984). Hypoxia, in turn, leads to the HIF-1α-dependent upregulation of methionine adenosyltransferase 2A, which is an enzyme that synthesizes S-adenosylmethionine, a major biological methyl donor critical for DNA methylation processes (Liu et al., 2011).


Cigarette smoking and DNA methylation.

Lee KW, Pausova Z - Front Genet (2013)

Effects of cigarette smoke exposure on DNA methylation. Cigarette smoke has been shown to modulate DNA methyltransferase 1 (DNMT1) content, both at the transcript and protein level, and enzymatic activity separately in different cell types. Double-stranded DNA breaks may be induced by cigarette smoke, which subsequently recruits DNMT1 adjacent to the repair site. DNA-binding proteins, such as Sp1, are activated by cigarette smoke and protect CpG sites from de novo methylation. In the context of prenatal exposure, cigarette smoke induces hypoxia in the embryo, which in turn modulates methyl group availability.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3713237&req=5

Figure 2: Effects of cigarette smoke exposure on DNA methylation. Cigarette smoke has been shown to modulate DNA methyltransferase 1 (DNMT1) content, both at the transcript and protein level, and enzymatic activity separately in different cell types. Double-stranded DNA breaks may be induced by cigarette smoke, which subsequently recruits DNMT1 adjacent to the repair site. DNA-binding proteins, such as Sp1, are activated by cigarette smoke and protect CpG sites from de novo methylation. In the context of prenatal exposure, cigarette smoke induces hypoxia in the embryo, which in turn modulates methyl group availability.
Mentions: Cigarette smoke is considered one of the most powerful environmental modifiers of DNA methylation (Breitling et al., 2011). The specific mechanisms of how cigarette smoke may alter DNA methylation are becoming better understood (Figure 2). First, cigarette smoke may modulate it through DNA damage and subsequent recruitment of DNMTs. Carcinogens in cigarette smoke, such as arsenic, chromium, formaldehyde, polycyclic aromatic hydrocarbons, and nitrosamines (Smith and Hansch, 2000; Suter et al., 2010), can damage DNA by causing double-stranded breaks, as shown in mouse embryonic stem cells exposed to cigarette-smoke condensate (Huang et al., 2012). In these experiments, survivor cells display a high capacity for DNA repair and normal karyotypes (Huang et al., 2012). The DNA repair sites recruit DNMT1 (Mortusewicz et al., 2005), which methylates CpGs adjacent to the repaired nucleotides (Cuozzo et al., 2007). Second, cigarette smoke may also modulate DNA methylation through nicotine effects on gene expression (Lee and D’Alonzo, 1993). Nicotine binds to and activates the nicotinic acetylcholine receptors (present abundantly in the central and peripheral nervous systems) and thus increases intracellular calcium and leads to downstream activation of cAMP response element-binding protein, a key transcription factor for many genes (Shen and Yakel, 2009). Acting possibly through this pathway, nicotine has been shown to downregulate DNMT1 mRNA and protein expression in mouse brain neurons (Satta et al., 2008). Third, cigarette smoke may alter DNA methylation indirectly through the modulation of expression and activity of DNA-binding factors. It has been demonstrated, for example, that cigarette-smoke condensate increases Sp1 expression and binding to DNA in lung epithelial cells (Mercer et al., 2009; Di et al., 2012). Sp1 is a common transcription factor that binds to GC-rich motifs in gene promoters (Kadonaga et al., 1987) and plays a key role in early development; as such, it may prevent de novo methylation of CpGs within these motifs during early embryogenesis (Han et al., 2001). Fourth, cigarette smoke may alter DNA methylation via hypoxia – cigarette smoke contains carbon monoxide that binds to hemoglobin (competitively with oxygen) and thus decreases tissue oxygenation (Olson, 1984). Hypoxia, in turn, leads to the HIF-1α-dependent upregulation of methionine adenosyltransferase 2A, which is an enzyme that synthesizes S-adenosylmethionine, a major biological methyl donor critical for DNA methylation processes (Liu et al., 2011).

Bottom Line: DNA methylation is a quantitative trait determined by a complex interplay of genetic and environmental factors.Genetic variants at a specific locus can influence both regional and distant DNA methylation.Epigenome-wide association studies have uncovered candidate genes associated with cigarette smoking that have biologically relevant functions in the etiology of smoking-related diseases.

View Article: PubMed Central - PubMed

Affiliation: Physiology and Experimental Medicine, The Hospital for Sick Children, University of Toronto Toronto, ON, Canada.

ABSTRACT
DNA methylation is the most studied epigenetic modification, capable of controlling gene expression in the contexts of normal traits or diseases. It is highly dynamic during early embryogenesis and remains relatively stable throughout life, and such patterns are intricately related to human development. DNA methylation is a quantitative trait determined by a complex interplay of genetic and environmental factors. Genetic variants at a specific locus can influence both regional and distant DNA methylation. The environment can have varying effects on DNA methylation depending on when the exposure occurs, such as during prenatal life or during adulthood. In particular, cigarette smoking in the context of both current smoking and prenatal exposure is a strong modifier of DNA methylation. Epigenome-wide association studies have uncovered candidate genes associated with cigarette smoking that have biologically relevant functions in the etiology of smoking-related diseases. As such, DNA methylation is a potential mechanistic link between current smoking and cancer, as well as prenatal cigarette-smoke exposure and the development of adult chronic diseases.

No MeSH data available.


Related in: MedlinePlus