Impact of the Genome on the Epigenome Is Manifested in DNA Methylation Patterns of Imprinted Regions in Monozygotic and Dizygotic Twins

University of Illinois at Chicago, United States of America
PLoS ONE (Impact Factor: 3.23). 10/2011; 6(10):e25590. DOI: 10.1371/journal.pone.0025590
Source: PubMed


One of the best studied read-outs of epigenetic change is the differential expression of imprinted genes, controlled by differential methylation of imprinted control regions (ICRs). To address the impact of genotype on the epigenome, we performed a detailed study in 128 pairs of monozygotic (MZ) and 128 pairs of dizygotic (DZ) twins, interrogating the DNA methylation status of the ICRs of IGF2, H19, KCNQ1, GNAS and the non-imprinted gene RUNX1. While we found a similar overall pattern of methylation between MZ and DZ twins, we also observed a high degree of variability in individual CpG methylation levels, notably at the H19/IGF2 loci. A degree of methylation plasticity independent of the genome sequence was observed, with both local and regional CpG methylation changes, discordant between MZ and DZ individual pairs. However, concordant gains or losses of methylation, within individual twin pairs were more common in MZ than DZ twin pairs, indicating that de novo and/or maintenance methylation is influenced by the underlying DNA sequence. Specifically, for the first time we showed that the rs10732516 [A] polymorphism, located in a critical CTCF binding site in the H19 ICR locus, is strongly associated with increased hypermethylation of specific CpG sites in the maternal H19 allele. Together, our results highlight the impact of the genome on the epigenome and demonstrate that while DNA methylation states are tightly maintained between genetically identical and related individuals, there remains considerable epigenetic variation that may contribute to disease susceptibility.

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Available from: Marcel Coolen, Oct 09, 2015
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    • "transmitted via the male germ line during more than three generations . Nonetheless , some epigenetic mechanisms might be controlled by heritable genetic effects . There are genotypes that are more susceptible to methylation than others ( Coolen et al . , 2011 ) . Such as genotypes with a larger proportion of cytosines in the CpG islands that are more susceptible to methylation . Further , DNA codes for histone and DNA - folding proteins , which may also have epigenetic effects . These sorts of elements with potential epigenetic effects are heritable in an additive manner . The challenge here"
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    ABSTRACT: This article reviews the concept of Lamarckian inheritance and the use of the term epigenetics in the field of animal genetics. Epigenetics was first coined by Conrad Hal Waddington (1905-1975), who derived the term from the Aristotelian word epigenesis. There exists some controversy around the word epigenetics and its broad definition. It includes any modification of the expression of genes due to factors other than mutation in the DNA sequence. This involves DNA methylation, post-translational modification of histones, but also linked to regulation of gene expression by non-coding RNAs, genome instabilities or any other force that could modify a phenotype. There is little evidence of the existence of transgenerational epigenetic inheritance in mammals, which may commonly be confounded with environmental forces acting simultaneously on an individual, her developing fetus and the germ cell lines of the latter, although it could have an important role in the cellular energetic status of cells. Finally, we review some of the scarce literature on the use of epigenetics in animal breeding programs.
    Frontiers in Genetics 09/2015; 6. DOI:10.3389/fgene.2015.00305
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    • "First, they have a known baseline level of methylation from which deviations are detectable; second, these regions are critical for the appropriate establishment and maintenance of imprinted gene expression; third, imprinted genes are essential for appropriate placental function, early development and growth; fourth, the DMRs exhibit parental origin-specific methylation profiles that are spatially and temporally stable such that methylation changes at imprinted gene DMRs resulting from in utero exposure to famine have been detected six decades postexposure (Heijmans et al., 2008); and last, these DMRs are known to exhibit shifts in methylation in response to a wide variety of other exposures, including maternal stress (Heijmans et al., 2008; Hochberg et al., 2011; Hoyo et al., 2011; Joubert et al., 2012; Murphy et al., 2012a; Timmermans et al., 2009; Tobi et al., 2009), and are widely deregulated in cancer (Sharma et al., 2010). The DMRs of many imprinted genes in humans have been characterized (Hoyo et al., 2011; Murphy et al., 2012b; Skaar et al., 2012; Woodfine et al., 2011) and provide relevant loci to investigate possible epigenetic responses resulting from environmental exposures (Coolen et al., 2011). "
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    ABSTRACT: Epigenetic processes, such as changes in DNA methylation, likely mediate the link between environmental exposures in utero and altered gene expression. Differentially methylated regions (DMRs) that regulate imprinted genes may be especially vulnerable to environmental exposures since imprinting is established and maintained largely through DNA methylation, resulting in expression from only one parental chromosome. We used the human embryonic kidney cell line, HEK-293, to investigate the effects of exposure to physiologically relevant doses of lead acetate (Pb) on the methylation status of nine imprinted gene DMRs. We assessed mean methylation after seventy-two hours of Pb exposure (0-25 μg/dL) using bisulfite pyrosequencing. The PEG1/MEST and IGF2 DMRs had maximum methylation decreases of 9.6% (20 μg/dL; p< 0.005) and 3.8% (25 μg/dL; p< 0.005), respectively. Changes at the MEG3 DMRs had a maximum decrease in methylation of 2.9% (MEG3) and 1.8% (MEG3-IG) at 5μg/dL Pb, but were not statistically significant. The H19, NNAT, PEG3, PLAGL1, and SGCE/PEG10 DMRs showed a less than 0.5% change in methylation for (across the dose range used), and were deemed non-responsive to Pb in our model. Pb exposure below reportable/actionable levels increased expression of PEG1/MEST concomitant with decreased methylation. These results suggest that Pb exposure can stably alter the regulatory capacity of multiple imprinted DMRs. Copyright © 2015. Published by Elsevier Ltd.
    Toxicology in Vitro 01/2015; 29(3). DOI:10.1016/j.tiv.2015.01.002 · 2.90 Impact Factor
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    • "n‐modifiable nucleotide , or indirect by altering transcription factor binding , which in turn independently affects gene expression and DNA methylation levels ( Gutierrez‐ Arcelus et al . , 2013 ) . Polymorphisms may also affect imprinting locus control regions and thus have an influence on epigenetic changes associated with parental imprinting ( Coolen et al . , 2011 ) . This concept of allele‐specific methylation is growing in importance with the recognition that this phenomenon may extend well beyond classical imprinted genes ."
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    ABSTRACT: Epigenetic mechanisms are proposed as an important way in which the genome responds to the environment. Epigenetic marks, including DNA methylation and Histone modifications, can be triggered by environmental effects, and lead to permanent changes in gene expression, affecting the phenotype of an organism. Epigenetic mechanisms have been proposed as key in plasticity, allowing environmental exposure to shape future gene expression. While we are beginning to understand how these mechanisms have roles in human biology and disease, we have little understanding of their roles and impacts on ecology and evolution. In this review, we discuss different types of epigenetic marks, their roles in gene expression and plasticity, methods for assaying epigenetic changes, and point out the future advances we require to understand fully the impact of this field. J. Exp. Zool. (Mol. Dev. Evol.) 9999B: 1–13, 2014. © 2014 Wiley Periodicals, Inc.
    Journal of Experimental Zoology Part B Molecular and Developmental Evolution 06/2014; 322(4). DOI:10.1002/jez.b.22571 · 2.31 Impact Factor
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