You will be presented with the abstract, introduction, and discussion section from a biomedical research article. Your task is to create a summary that a layperson can understand, capturing the essence of the research article. Keep essential scientific terms, but ensure that the language remains clear and the concepts are explained in an uncomplicated manner.

Title: A survey of inter-individual variation in DNA methylation identifies environmentally responsive co-regulated networks of epigenetic variation in the human genome}
Article:
Abstract:
While population studies have resulted in detailed maps of genetic variation in humans, to date there are few robust maps of epigenetic variation. We identified sites containing clusters of CpGs with high inter-individual epigenetic variation, termed Variably Methylated Regions( VMRs) in five purified cell types. We observed that VMRs occur preferentially at enhancers and 3’ UTRs. While the majority of VMRs have high heritability, a subset of VMRs within the genome show highly correlated variation in trans, forming co-regulated networks that have low heritability, differ between cell types and are enriched for specific transcription factor binding sites and biological pathways of functional relevance to each tissue. For example, in T cells we defined a network of 95 co-regulated VMRs enriched for genes with roles in T-cell activation; in fibroblasts a network of 34 co-regulated VMRs comprising all four HOX gene clusters enriched for control of tissue growth; and in neurons a network of 18 VMRs enriched for roles in synaptic signaling. By culturing genetically-identical fibroblasts under varying environmental conditions, we experimentally demonstrated that some VMR networks are responsive to the environment, with methylation levels at these loci changing in a coordinated fashion in trans dependent on cellular growth. Intriguingly these environmentally-responsive VMRs showed a strong enrichment for imprinted loci( p<10−80), suggesting that these are particularly sensitive to environmental conditions. Our study provides a detailed map of common epigenetic variation in the human genome, showing that both genetic and environmental causes underlie this variation.
Introduction:
Understanding the causes and consequences of genomic variation among humans is one of the major goals in the field of genetics. Over the past decade, studies such as the Hapmap and 1000 Genomes Projects have resulted in detailed maps of genetic variation in diverse human populations, identifying millions of single nucleotide polymorphisms, copy number variants and other types of sequence variation[1–6]. These maps have acted as the catalysts for thousands of genome-wide association studies[7], and have provided insights into diverse processes such as mechanisms of human disease, mutation, evolution, migration, selection and recombination[8–11]. However, alterations of the primary DNA sequence are not the only type of genomic variations that occur among humans. In particular there are now well-documented examples of epigenetic marks, such as DNA methylation and histone modifications, that show significant inter-individual variation[12–14]. However, in contrast to sequence polymorphism, relatively few studies have examined the distribution of epigenetic variation across the genome, and as a result our understanding of the causes and consequences of epigenetic polymorphism remains limited. Familial and twin studies in human and mice[12, 13, 15–20] have shown that a substantial fraction of sites showing variable DNA methylation levels are highly heritable, and for some loci this epigenetic polymorphism has been linked with nearby genetic variation[21–24]. However, these same studies have also demonstrated that a subset of methylation variation exhibits low heritability[12, 16–18, 25]. While stochastic variation or technical variability could explain reduced heritability levels, differing environmental exposures such as smoking[26–28], diet/in-utero environment[29–31] and stress[32–35] have all been shown to modify the epigenome. In addition, other natural processes such as aging and X chromosome inactivation apparently underlie epigenetic variation of some sites[36–38]. Whatever the root cause of epigenetic polymorphism, several studies have demonstrated that a subset of these variations are functionally significant and associate with the expression levels of nearby genes[23, 39]. Accordingly there is now substantial interest in elucidating the role of epigenetic variation in a variety of disease phenotypes[40–48], indicating that the study of epigenetic polymorphism holds significant promise for understanding the molecular etiology of disease. In this study, we have performed a screen to identify regions of common epigenetic variation using population data derived from five different human cell types. By searching for clusters of probes with high inter-individual variability, we uncover hundreds of loci in the human genome that exhibit highly polymorphic DNA methylation levels that we term variably methylated regions( VMRs). We show that VMRs co-localize with other functional genomic features, are enriched for CpGs that influence gene expression, and provide evidence that epigenetic variability at some of these loci is influenced by both genetic and environmental factors. We also show that VMRs form cis and trans co-regulated networks enriched for transcription factor binding sites and genes with cell-type relevant functions. Finally, consistent with the notion that the epigenome represents a dynamic link between our genome and the environment[49, 50], we experimentally demonstrate environmental effects on methylation at VMRs using cultured fibroblasts, revealing signatures that overlap those observed in our population-level datasets. Together, our results provide novel insights into the biology of variable methylation across the human genome.
Discussion:
Here we surveyed variation in DNA methylation patterns in five purified human cell types, identifying hundreds of genomic loci that exhibit a high degree of epigenetic polymorphism in the human population: we term these ‘Variably Methylated Regions’ or VMRs. We observed that VMRs are enriched for various functional genomic features, most notably enhancers, suggesting a potential role in regulating gene expression patterns. Unexpectedly, we found that many VMRs form co-regulated networks both in cis and in trans, with multiple VMRs spread across different chromosomes at which methylation levels vary in a coordinated fashion. These co-regulated networks were specific to each cell type, had reduced heritability, and were also enriched for gene sets with cell-type relevant functions. For example, we observed VMR networks associated with genes enriched for synaptic transmission in neurons, regulation of nervous system development in glia, and T cell activation in T cells. These observations suggest that some VMRs represent loci that form co-regulated pathways that are implicated in the regulation of genes with cell-type specific functions. The dispersed nature of these co-regulated VMR networks indicates that they are potentially regulated by trans acting factors, and consistent with this we found significant enrichments for relevant transcription factor binding sites associated with some networks. While many VMRs are influenced by local genotypes, our analyses of monozygotic twins, a cohort of African samples conceived in divergent nutritional environments, and in-vitro culture of genetically identical fibroblasts cell lines indicates that epigenetic variation at some VMRs is linked to environmental factors. Indeed, using isogenic fibroblast cultures derived from a single individual that were grown under different environmental conditions, we were able to replicate many of the same VMRs found in our original population analysis, thus showing that epigenetic variation at these loci is an environmentally inducible trait. Intriguingly these environmentally-responsive VMRs showed a strong enrichment for imprinted loci( p<10−94), suggesting that these genes are particularly sensitive to environmental conditions. This observation that varying cell culture conditions result in epigenetic alterations across the genome, presumably accompanied by changes in gene expression, highlights that the use of cultured cells for investigating epigenetic phenomena should be approached with caution. We suggest that unless carefully controlled, variations in cell culture conditions could easily introduce significant epigenetic and transcriptional changes that could confound many in vitro studies. VMRs in fibroblasts comprised co-regulated modules that included all four HOX gene clusters that are each located on different chromosomes. While a previous study has reported that the HOX genes exhibit variable methylation that correlates with their expression levels[53], our analysis builds on these observations by showing that methylation across multiple HOX gene clusters is correlated in both cis and trans. Furthermore, using validated transcription factor binding sites, we found a significant enrichment for transcription factors EZH2 and SUZ12 at these VMR sites associated with HOX genes. These two transcription factors are components of the Polycomb Repressive Complex 2( PRC2), which functions as a histone H3K27-specific methyltransferase and regulates both epigenetics and expression of HOX genes[66]. Thus, we propose a model where coordinated variation of DNA methylation at multiple loci in trans, corresponding to a network of co-regulated genes, is under the control of transcription factor binding in response to physiological and/or environmental cues. In the case of the HOX gene network in cultured fibroblast cell lines, such cues could be the availability of nutrients, local cell density and other growth conditions, allowing the cells to modify their growth trajectories in response to the prevailing environment. Consistent with this model, recent observations were made in macrophages, a type of immune cell that has a variety of roles in different tissues around the body, which mirror our findings. Two prior studies showed that the epigenetic state of enhancer elements in these cells responds to the tissue microenvironment in which they reside, and is regulated by networks of tissue- and lineage-specific transcription factors that drive divergent programs of gene expression[69, 70]. Studies of chromatin accessibility have also shown that manipulating the presence of specific transcription factors can lead to global modification of epigenetic state at multiple loci in trans[71]. We defined VMRs as clusters of probes with high variance, as the use of single probes to determine epigenetic variability is inherently unreliable. This is because other phenomena unrelated to epigenetic variance can influence the β-value reported by a probe, independent of DNA methylation levels. These include, for example, underlying genetic variants that alter probe binding, random technical effects such as hybridization or wash artifacts on the array, or the simple fact that some probes might simply perform poorly and yield inherently more variable results. By considering groups of multiple closely spaced probes that all show high variability makes it much less likely that our results would be influenced by the effects listed above, thus improving specificity for the detection of true epigenetic variability, and reducing artifacts. One of the strengths of this study is that we specifically utilized purified cell types for our analysis, some of which were also of homogeneous age. This has the advantage of removing the confounder of both cellular heterogeneity and age effects, both of which are known to influence DNA methylation[36, 37, 72]. Such differences would otherwise result in many false positive VMRs due to underlying differences in cell fractions or age among individuals. One of the limitations of this analysis is that we used methylation profiles from the Illumina 450k array, which targets only a small subset( ~3%) of CpGs in the human genome, and has coverage that is biased towards gene promoters and CpG islands. As such, the maps of VMRs we provide here are far from comprehensive, and future work that utilizes more comprehensive approaches( e. g. whole genome bisulfite sequencing) will undoubtedly provide more complete genomic maps of epigenetic variation. However, to our knowledge currently no such datasets on a population-scale are available. One other potential caveat is that the methylation profiles for B cells, fibroblasts and T cells were all generated from cells that had been cultured in vitro, and furthermore the B cells were also immortalized by Epstein-Barr virus infection, a process which is known to induce widespread epigenetic changes[73]. However, we observed good replication of the VMRs identified from cultured/immortalized B cells and T cells in an independent cohort where DNA was extracted from uncultured blood, indicating that many of these same VMRs observed even in immortalized B cells are also present natively. One confounder that deserves mention is that there is potential that some of the enrichments we identify between VMR probes and factors such as mQTLs and eQTMs could be driven by the inherent variability of VMRs. This is because statistical power to identify an association with a locus is heavily influenced by the underlying variability of that site. Thus, it is possible that some of enrichments we observe are due either partly or wholly to this effect. Similarly, it is also possible that the increased discordance we observed in MZ twin pairs at VMRs might be driven simply by the higher variability of methylation at these loci. In conclusion our study of DNA methylation polymorphism provides novel insights into the nature and function of epigenetic variation. The coordinated phenomenon we observed where methylation levels at networks of multiple genomic regions varies in response to the local environment is consistent with popular theories that the epigenome can indeed act as an interface between the genome and environment[39, 50, 74].
Multiple published studies have demonstrated that epigenetic variation can contribute to phenotypic variation . In the present study , we identified regions of common methylation variation in five cell types , observing that these show enrichments for functional genomic features . Surprisingly , we found that these epigenetic variations can form biologically relevant networks that are specific to each cell type , often occurring near genes that have functional relevance to the cell type . Further these regions show reduced heritability , suggesting they may be responsive to environmental cues . We confirmed this by subjecting isogenic fibroblast cultures to different environmental stress . Our study provides insight into patterns of normal epigenetic variation in the human population .