A twin approach to unraveling epigenetics

The regulation of gene expression plays a pivotal role in complex phenotypes, and epigenetic mechanisms such as DNA methylation are essential to this process. The availability of next-generation sequencing technologies allows us to study epigenetic variation at an unprecedented level of resolution. Even so, our understanding of the underlying sources of epigenetic variability remains limited. Twin studies have played an essential role in estimating phenotypic heritability, and these now offer an opportunity to study epigenetic variation as a dynamic quantitative trait. High monozygotic twin discordance rates for common diseases suggest that unexplained environmental or epigenetic factors could be involved. Recent genome-wide epigenetic studies in disease-discordant monozygotic twins emphasize the power of this design to successfully identify epigenetic changes associated with complex traits. We describe how large-scale epigenetic studies of twins can improve our understanding of how genetic, environmental and stochastic factors impact upon epigenetics, and how such studies can provide a comprehensive understanding of how epigenetic variation affects complex traits. The regulation of gene expression plays a pivotal role in complex phenotypes, and epigenetic mechanisms such as DNA methylation are essential to this process. The availability of next-generation sequencing technologies allows us to study epigenetic variation at an unprecedented level of resolution. Even so, our understanding of the underlying sources of epigenetic variability remains limited. Twin studies have played an essential role in estimating phenotypic heritability, and these now offer an opportunity to study epigenetic variation as a dynamic quantitative trait. High monozygotic twin discordance rates for common diseases suggest that unexplained environmental or epigenetic factors could be involved. Recent genome-wide epigenetic studies in disease-discordant monozygotic twins emphasize the power of this design to successfully identify epigenetic changes associated with complex traits. We describe how large-scale epigenetic studies of twins can improve our understanding of how genetic, environmental and stochastic factors impact upon epigenetics, and how such studies can provide a comprehensive understanding of how epigenetic variation affects complex traits. The term epigenetics was originally introduced to describe how interactions between genetics and environment can give rise to phenotypes during development 1Waddington C.H. The epigenotype.Endeavour. 1942; 1: 18-20Crossref Google Scholar. Epigenetics today more specifically defines cellular modifications that can be heritable, but appear unrelated to DNA sequence changes, and can be modified by environmental stimuli 2Holliday R. Epigenetics: an overview.Dev. Genet. 1994; 15: 453-457Crossref Google Scholar, 3Russo V.E.A. et al.Epigenetic Mechanisms of Gene Regulation. Cold Spring Harbor Laboratory Press, 1996Google Scholar. At present, epigenetic mechanisms typically comprise DNA methylation and histone modifications, but also include many other mechanisms such as ATP-based chromatin-remodeling complexes, Polycomb–Trithorax protein complexes, non-coding RNA mediated gene-silencing, and potentially prions, transcription-factor binding, and other mechanisms involved in generating and maintaining heritable chromatin structure and attachment to the nuclear matrix. Epigenetic mechanisms play an essential functional role in complex organisms as regulators of transcription. Central to epigenetic regulation is the modulation of chromatin structure, whereby the majority of epigenetic processes impact upon chromatin organization and maintenance. Next-generation sequencing technologies have been developed to assay epigenetic changes (Box 1) in high-throughput approaches, and high-resolution genome-wide epigenetic profiles promise a more complete understanding of the functional impact of epigenetics. Of these processes, DNA methylation is the mechanism that has been studied in the greatest depth, and we therefore focus predominantly on this mechanism in this review.Box 1Next-generation sequencing technologies applied to epigeneticsThe availability of next-generation sequencing technologies has recently allowed the survey of genome-wide epigenetic variation at high resolution 8Bock C. et al.Quantitative comparison of genome-wide DNA methylation mapping technologies.Nat. Biotechnol. 2010; 28: 1106-1114Crossref PubMed Scopus (225) Google Scholar, 99Harris J.R. et al.Sources of epigenetic variation at the MHC.Twin Res. Hum. Genet. 2010; 13: 262Google Scholar, 104Laird P.W. The power and the promise of DNA methylation markers.Nat. Rev. Cancer. 2003; 3: 253-266Crossref PubMed Google Scholar, 105Thu K.L. et al.Methylated DNA immunoprecipitation.J. Cell Physiol. 2009; 222: 522-531Google Scholar. We describe some of these approaches briefly below. In addition, single-molecule sequencing technologies (e.g. 106Flusberg B.A. et al.Direct detection of DNA methylation during single-molecule, real-time sequencing.Nat. Methods. 2010; 7: 461-465Crossref PubMed Scopus (285) Google Scholar) an more complex and of epigenetic mechanisms and sequencing and are on of the DNA by are to therefore complete is to the of the between and approaches survey DNA methylation the or in a of the to be for of DNA sequencing DNA by sequencing and DNA sequencing are on of the of the by or protein binding, by and In some of these technologies the of a DNA but that this have been developed et for DNA Biotechnol. PubMed Scopus Google Scholar]. of the is the to design to the detection of and sequencing typically DNA and DNA with such as and to DNA by by sequencing is the to non-coding can be studies by RNA that are and are protein the of protein to be non-coding typically a and RNA sequencing structure technologies have been to assay chromatin structure and include in are et mapping and of chromatin the PubMed Scopus Google or of by in DNA is chromatin et of chromatin in Genet. 2010; PubMed Scopus (225) Google of chromatin is by sequencing et chromatin 2009; Scopus Google or sequencing and approaches et PubMed Scopus Google Scholar, et a for mapping interactions between Res. PubMed Scopus Google Scholar, et organization of and chromatin by Genet. PubMed Scopus Google Scholar, et assay chromatin Res. Scopus Google and The availability of next-generation sequencing technologies has recently allowed the survey of genome-wide epigenetic variation at high resolution 8Bock C. et al.Quantitative comparison of genome-wide DNA methylation mapping technologies.Nat. Biotechnol. 2010; 28: 1106-1114Crossref PubMed Scopus (225) Google Scholar, 99Harris J.R. et al.Sources of epigenetic variation at the MHC.Twin Res. Hum. Genet. 2010; 13: 262Google Scholar, 104Laird P.W. The power and the promise of DNA methylation markers.Nat. Rev. Cancer. 2003; 3: 253-266Crossref PubMed Google Scholar, 105Thu K.L. et al.Methylated DNA immunoprecipitation.J. Cell Physiol. 2009; 222: 522-531Google Scholar. We describe some of these approaches briefly below. In addition, single-molecule sequencing technologies (e.g. 106Flusberg B.A. et al.Direct detection of DNA methylation during single-molecule, real-time sequencing.Nat. Methods. 2010; 7: 461-465Crossref PubMed Scopus (285) Google Scholar) an more complex and of epigenetic mechanisms and sequencing and are on of the DNA by are to therefore complete is to the of the between and approaches survey DNA methylation the or in a of the to be for of DNA sequencing DNA by sequencing and DNA sequencing are on of the of the by or protein binding, by and In some of these technologies the of a DNA but that this have been developed et for DNA Biotechnol. PubMed Scopus Google Scholar]. of the is the to design to the detection of and sequencing typically DNA and DNA with such as and to DNA by by sequencing is the to non-coding can be studies by RNA that are and are protein the of protein to be non-coding typically a and RNA sequencing Recent technologies have been to assay chromatin structure and include in are et mapping and of chromatin the PubMed Scopus Google or of by in DNA is chromatin et of chromatin in Genet. 2010; PubMed Scopus (225) Google of chromatin is by sequencing et chromatin 2009; Scopus Google or sequencing and approaches et PubMed Scopus Google Scholar, et a for mapping interactions between Res. PubMed Scopus Google Scholar, et organization of and chromatin by Genet. PubMed Scopus Google Scholar, et assay chromatin Res. Scopus Google and Epigenetic mechanisms are in many but DNA methylation has been studied in to be to the and in the of are that typically in to as are in gene and of DNA DNA methylation in can also the and this has been for in et methylation is in and be mediated by DNA Scopus Google Scholar]. is typically to can also be to could also play an epigenetic role The nuclear DNA is in and the 2009; PubMed Scopus Google Scholar]. In DNA methylation is mediated by DNA that are for methylation and the of methylation during Rev. PubMed Scopus Google and also by DNA that are for genome-wide of DNA methylation (Box and methylation have high between et of to DNA methylation and of epigenetic Biotechnol. 2010; 28: PubMed Scopus Google and between and 8Bock C. et al.Quantitative comparison of genome-wide DNA methylation mapping technologies.Nat. Biotechnol. 2010; 28: 1106-1114Crossref PubMed Scopus (225) Google Scholar, et for DNA Biotechnol. 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