Identification of Genetic Variants That Affect Histone Modifications in Human Cells

McVicker, Graham; Geijn, Bryce van de; Degner, Jacob F.; Cain, Carolyn E.; Banovich, Nicholas E.; Raj, Anil; Lewellen, Noah; Myrthil, Marsha; Gilad, Yoav; Pritchard, Jonathan K.

doi:10.1126/science.1242429

Cited by 440 publications

(434 citation statements)

References 42 publications

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“…However, the effect is likely mediated by the sequence-specific binding of proteins and alteration of chromatin factors that subsequently affects binding of de novo methylases or demethylating mechanisms. A similar mechanism has been evidenced for other epigenetic marks, recently shown to be affected by polymorphism in a similar way to methylation (Otani et al 2009;Kasowski et al 2013;Kilpinen et al 2013;McVicker et al 2013). A study of these other epigenomic marks in a similar context to that we describe for DNA methylation would be fascinating.…”

Section: Discussionmentioning

confidence: 85%

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The effect of genotype and in utero environment on interindividual variation in neonate DNA methylomes

et al. 2014

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Integrating the genotype with epigenetic marks holds the promise of better understanding the biology that underlies the complex interactions of inherited and environmental components that define the developmental origins of a range of disorders. The quality of the in utero environment significantly influences health over the lifecourse. Epigenetics, and in particular DNA methylation marks, have been postulated as a mechanism for the enduring effects of the prenatal environment. Accordingly, neonate methylomes contain molecular memory of the individual in utero experience. However, interindividual variation in methylation can also be a consequence of DNA sequence polymorphisms that result in methylation quantitative trait loci (methQTLs) and, potentially, the interaction between fixed genetic variation and environmental influences. We surveyed the genotypes and DNA methylomes of 237 neonates and found 1423 punctuate regions of the methylome that were highly variable across individuals, termed variably methylated regions (VMRs), against a backdrop of homogeneity. MethQTLs were readily detected in neonatal methylomes, and genotype alone best explained~25% of the VMRs. We found that the best explanation for 75% of VMRs was the interaction of genotype with different in utero environments, including maternal smoking, maternal depression, maternal BMI, infant birth weight, gestational age, and birth order. Our study sheds new light on the complex relationship between biological inheritance as represented by genotype and individual prenatal experience and suggests the importance of considering both fixed genetic variation and environmental factors in interpreting epigenetic variation.

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Section: Discussionmentioning

confidence: 85%

“…5). There is recent evidence that epigenetic states may serve to directly mediate the relation between certain genetic polymorphisms and phenotype (McVicker et al 2013). The mechanism by which sequence polymorphism affects local CpG methylation is unknown (assuming the SNP is not within the CpG, a situation we have labeled disrupting pairs).…”

Section: Discussionmentioning

confidence: 99%

The effect of genotype and in utero environment on interindividual variation in neonate DNA methylomes

et al. 2014

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“…Family-and population-level genetic analyses have described the association of DNA sequence variants with altered histone modification patterns (38)(39)(40), suggesting a causal role of sequence-specific factors in determining chromatin state. The genetic inheritance of DNA sequence variants has also been suggested to be the primary cause of allele-specific variations in levels of DNA methylation (41).…”

Section: Discussionmentioning

confidence: 99%

Transcription factor binding predicts histone modifications in human cell lines

Benveniste

Sonntag

Sanguinetti

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

113

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Gene expression in higher organisms is thought to be regulated by a complex network of transcription factor binding and chromatin modifications, yet the relative importance of these two factors remains a matter of debate. Here, we show that a computational approach allows surprisingly accurate prediction of histone modifications solely from knowledge of transcription factor binding both at promoters and at potential distal regulatory elements. This accuracy significantly and substantially exceeds what could be achieved by using DNA sequence as an input feature. Remarkably, we show that transcription factor binding enables strikingly accurate predictions across different cell lines. Analysis of the relative importance of specific transcription factors as predictors of specific histone marks recapitulated known interactions between transcription factors and histone modifiers. Our results demonstrate that reported associations between histone marks and gene expression may be indirect effects caused by interactions between transcription factors and histone-modifying complexes.epigenetics | gene regulation G ene expression is the fundamental process through which genetic information is dynamically and specifically deployed within cells. It is, therefore, of vital importance to all organisms and tightly controlled at both the transcriptional and posttranscriptional levels. Consequently, the elucidation of generegulatory mechanisms has been a central focus of biological research, with the area of transcriptional regulation having attracted intense attention over the last four decades.The canonical players in transcriptional regulation are sequence-specific DNA-binding transcription factors (TFs) that modulate gene expression by facilitating or inhibiting the recruitment of RNA polymerase to gene promoters (1). This paradigm has provided a powerful unifying mechanism for transcription, validated by a large amount of experimental evidence over the last five decades (see, e.g., ref. 2). Further evidence of the power of TFs to act as master regulators of gene expression and cell identity is illustrated by their ability to reprogram differentiated fibroblasts into embryonic stem (ES) cells (3).Research in the field of epigenetics has, however, suggested an alternative view that places posttranslational modifications of the histone subunits of nucleosomes in a central role of transcriptional regulation. The finding that particular combinations of histone modifications are associated with active and repressed gene promoters (4) has led to suggestions that a histone code controls gene expression (5, 6). Support for this hypothesis has come from the recent application of bioinformatic approaches to whole-genome measurements of both histone modifications and gene expression, which have demonstrated that gene expression can be predicted from histone modifications (7,8). This model has generated intense interest and is part of the stimulation behind the search for epigenetic causes of human disease (9).However, although histone mo...

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“…Additional research further explored the molecular determinants that contribute to cell-type specificity Mortazavi et al 2013), including the identification of sequence variants that drive changes to the epigenome (McVicker et al 2013) and genomic hallmarks that predict active TF binding sites (Savic et al 2015b). However, these in vitro systems are likely to be limited in the extent to which they recapitulate in vivo tissue environments, especially for noncancerous tissues (Sandberg and Ernberg 2005;Ertel et al 2006).…”

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confidence: 99%

A genome-wide interactome of DNA-associated proteins in the human liver

et al. 2017

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Large-scale efforts like the ENCODE Project have made tremendous progress in cataloging the genomic binding patterns of DNA-associated proteins (DAPs), such as transcription factors (TFs). However, most chromatin immunoprecipitation-sequencing (ChIP-seq) analyses have focused on a few immortalized cell lines whose activities and physiology differ in important ways from endogenous cells and tissues. Consequently, binding data from primary human tissue are essential to improving our understanding of in vivo gene regulation. Here, we identify and analyze more than 440,000 binding sites using ChIP-seq data for 20 DAPs in two human liver tissue samples. We integrated binding data with transcriptome and phased WGS data to investigate allelic DAP interactions and the impact of heterozygous sequence variation on the expression of neighboring genes. Our tissue-based data set exhibits binding patterns more consistent with liver biology than cell lines, and we describe uses of these data to better prioritize impactful noncoding variation. Collectively, our rich data set offers novel insights into genome function in human liver tissue and provides a valuable resource for assessing disease-related disruptions.

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Identification of Genetic Variants That Affect Histone Modifications in Human Cells

Cited by 440 publications

References 42 publications

The effect of genotype and in utero environment on interindividual variation in neonate DNA methylomes

The effect of genotype and in utero environment on interindividual variation in neonate DNA methylomes

Transcription factor binding predicts histone modifications in human cell lines

A genome-wide interactome of DNA-associated proteins in the human liver

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