Genetics Driving Epigenetics

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Science  08 Nov 2013:
Vol. 342, Issue 6159, pp. 705-706
DOI: 10.1126/science.1246755

Humans vary according to a plethora of traits, such as height, hair color, behavior, and susceptibility to disease. Both genetics (nature) and environment (nurture) contribute to this variation. Recent large-scale genetic studies have identified thousands of specific DNA variations in the human population that are associated with different traits. However, these studies do not answer a key question: By what means do most DNA variants alter cellular behavior and contribute to differences in specific traits, such as height? A trio of papers in this issue by Kasowski et al. on page 750 (1), Kilpinen et al. on page 744 (2), and McVicker et al. on page 747 (3) provide a framework for exploring the mechanistic link between genetic and trait variation in the human population. Specifically, they find that DNA variants influence a layer of gene regulation called epigenetics through the sequence-specific activity of transcription factors.

One of the most important discoveries in genetics in the last 10 years is that the vast majority of trait-associated DNA variations occur in regions of the genome that were once labeled as “junk DNA” because they do not code for proteins. We now know that these regions harbor genetic elements that control where, when, and to what extent specific genes are expressed to make functional RNA and protein products. Therefore, most trait-associated DNA variants are thought to alter not the gene itself, but rather, the regulatory elements that control the process of gene expression. In the last 3 years, several gene-regulatory variants have been strongly implicated in traits such as blood cholesterol concentrations (4) and diseases such as diabetes (5, 6), osteoarthritis (7), and prostate cancer (8). Despite these advances, precisely how most regulatory variants alter gene expression has been poorly understood.

Epigenetic mechanisms are known to control heritable gene expression but have been generally viewed as independent of the underlying DNA sequence. DNA is packaged in a three-dimensional structure, chromatin, whose basic repeating unit, the nucleosome, consists of ∼146 nucleotides of DNA wrapped around an octamer of specialized proteins called histones. Each of the eight histone proteins has amino acid “tails” that stick out from the nucleosome. Specific amino acids in these tails are subject to a vast array of chemical modifications, such as methylation, acetylation, or phosphorylation, which are carried out by a variety of nuclear enzymes. The “histone code hypothesis” (9) proposes that specific combinations of histone tail modifications (epigenetic marks) are associated with transcription factors that increase or decrease gene expression.

Human trait variation.

(A) Differences in a human trait (such as height) are partly due to the combined effects of genetic variants that alter the expression of multiple genes. (B) At a specific genomic position, a nucleotide [such as adenine (A)] is associated with accessible DNA, which facilitates transcription factor binding. This step leads to histone tail modifications that promote a chromatin environment favorable for the expression of neighboring genes. (C) At the same genomic position, a nucleotide variant [such as guanine (G)] has low affinity for transcription factor binding, which leads to a chromatin environment unfavorable for gene expression. Pol II, polymerase II


Kasowski et al., Kilpinen et al., and McVicker et al. perform integrative analysis of diverse data types generated from lymphoblastoid cell lines across numerous individuals and family trios. They demonstrate that histone tail modifications are highly variable in the human population and that they are heritable across generations. The studies identified hundreds of DNA variants that are associated with both histone tail modification and gene expression variation, indicating that genetics coordinates epigenetic effects on gene regulation. But how does variation in the DNA sequence influence chemical modification at histone tails? The three studies point to transcription factor activity as the missing link.

Most transcription factors bind directly to DNA, each with a preference for a particular DNA sequence pattern. Some DNA variants can substantially alter transcription factor binding affinity at particular genomic locations and thereby influence gene transcription. Kasowski et al., Kilpinen et al., and McVicker et al. used computationally predicted and empirically determined transcription factor binding data to identify hundreds of DNA variants that affect the strength of transcription factor binding. Many of these variants were also associated with variation in histone tail modifications.

These findings suggest a mechanism in which transcription factor binding to DNA initiates the recruitment of histone-modifying enzymes that set the histone tail modification pattern. Thus, a possible model (see the figure) is that trait-associated variants, most of which are gene regulatory in nature, affect the recruitment and binding of transcription factors to DNA. Differential transcription factor binding leads to variable histone tail modifications that collectively influence gene expression. Gene expression variations can manifest as trait differences.

Among some of the distinct findings of the studies, McVicker et al. showed that a single DNA variant can influence histone modifications at multiple related regions in the genome, providing information on their functional relationships. Kasowski et al. found that an individual's ancestry can affect what genomic regions exhibit genetically driven variability in chromatin marks. Kilpinen et al. noted that coordinated effects of DNA variation extend beyond transcription factor binding and histone tail modifications to other aspects of gene regulation, such as rate of transcription. Interestingly, all three studies found that many of the DNA variants associated with both transcription factor binding and histone tail modification variability were not associated with gene expression variability. This suggests that there is an abundance of nonconsequential regulatory variation, and/or that there are widespread mechanisms to compensate for the effects of regulatory variation, and/or that the regulatory effects of some transcription factor binding events are evident only under specific environmental conditions that are not well captured in cell culture.

The studies of Kasowski et al., Kilpinen et al., and McVicker et al. provide new insight into genetic mechanisms that affect complex traits and disease, and also elucidate basic gene-regulatory processes, but by no means is either of these problems solved. For example, as the authors of these three studies emphasize, not every regulatory variant will lead to trait differences or even gene expression differences. Why are some regulatory variants more critical than others for trait variability or disease risk? There is much more to uncover to answer this and related questions, but these studies bring us one step closer and provide a framework for exploring this topic further.

References and Notes

  1. Acknowledgments: We thank S. Kelada, M. Deshmukh, P. Rajasethupathy, M. Stitzel, and A. Laederach for critical reading and discussion.
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