Overview – gene regulatory evolution

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Regulatory landscapes defined by integrated epigenetic profiling

Gene expression is controlled by non-coding regulatory elements, which include promoters, enhancers, and regulatory RNAs. Thanks to major technological advances over the past decade, high-resolution genomic “maps” of regulatory elements have been generated across hundreds of different cell types and tissues, across individuals and even across single cells. Motivating this massive data production effort is the increased recognition that mutations affecting regulatory sequences are a major driver of both disease and adaptation.

While there have been great strides in our ability to map genomic regulatory landscapes, we know very little about how these landscapes were shaped by evolution and selection. How are regulatory elements “born” and what rules govern their conservation or divergence as species diverge? Our research integrates genomic analyses and experimental studies to address questions related to the mechanisms of regulatory evolution. Some of our major research areas are listed below.


Transposons and the evolution of immune regulatory networks

Transposons are genetic sequences that function only to selfishly copy themselves within host DNA. Transposons can be thought of as the ultimate parasites, and are so successful that they are found in nearly all organisms, from bacteria to plants to mammals. Over 50% of our own genomic sequence is composed of repetitive sequence fragments of transposon origin.

How has this eons-long battle over our own genomes impacted our biology and evolution? We have been investigating a novel role for transposons in the regulation of innate immune responses, taking advantage of the rich genomic and experimental resources available to investigate immunological pathways.

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Meta-analysis on transposon activity

Our work has revealed that endogenous retroviruses, a type of transposon originating from past retroviral infections, has distributed thousands of regulatory elements that become active during cellular infection. We identified MER41, an ancient retrovirus that invaded the genomes of our primate ancestors over 50 million years ago. Through genomic analysis and generation of CRISPR knockouts, we discovered several copies of the MER41 retrovirus that have been evolutionarily “domesticated” to regulate important immune defense genes, including the antiviral gene AIM2.

We are now investigating whether this phenomenon is the “tip of the iceberg.” Were these rare events, or is the co-option of retroviruses a more general mechanism that facilitates “wiring” of mammalian immune responses? If so, why are retroviruses such a potent source of immune-inducible regulatory sequences?

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Viruses related to MER41 have independently invaded other mammalian genomes.

Chuong EB, Elde NC*, Feschotte C*. Regulatory evolution of innate immunity through co-option of endogenous retroviruses. Science (2016) vol. 351: 1083-1087

Chuong EB, Elde NC, Feschotte C. Regulatory activities of transposable elements: from conflicts to benefits. Nature Reviews Genetics (2017) 18: 71-86


Transposons and pathogenic gene regulatory networks

Although transposons are occasionally co-opted for beneficial host functions, they are much more likely to impose a neutral or deleterious cellular effect. To cope with the constant barrage of transposons, we have evolved several genomic defenses to repress transposon activity through epigenetic means such as DNA methylation. However, these mechanisms are weakened when the cell is in a diseased state, and global reactivation of normally-silenced transposons has been extensively documented in many types of cancers and autoimmune disorders.

Re-activated “zombie” transposons can cause havoc in the cell through a number of different mechanisms, including transposing into and breaking tumor suppressors, or inappropriately triggering autoimmune responses. Less well studied is their impact on host gene regulation, which could potentially be very widespread. We are investigating the hypothesis that transposons are a major contributor to pathogenic gene regulation in diseased states. disease


Rapid evolution of the mammalian placenta

The mammalian placenta is a recent evolutionary innovation that allowed for direct maternal-fetal interactions during pregnancy. Although pregnancy is commonly thought of as a harmonious interaction between mother and fetus, a long-standing hypothesis proposes that there is an inherent evolutionary conflict between parent and offspring, which are necessarily genetically distinct (David Haig, Robert Trivers). Locked in evolutionary battle, the fetal placenta faces inherent evolutionary pressure to selfishly maximize its share of maternal resources. Consistent with this idea, the placenta exhibits striking morphological diversity across species and exhibits patterns of gene evolution reminiscent of the immune system (Chuong, Tong, Hoekstra MBE 2010). We are interested in studying placenta evolution from this “parasitic” point of view, in hopes of advancing our understanding of this relatively understudied organ.

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A family of endogenous retroviruses has dispersed hundreds of enhancers with  placenta-specific activity.

An intriguing observation made in nearly all mammals is the abundant expression of endogenous retroviruses in the placenta. We profiled placental enhancer landscapes between mouse and rat using chromatin immunoprecipitation (ChIP)-Seq, uncovering hundreds of mouse-specific enhancers derived from a mouse-specific endogenous retroviruses. The activity of these enhancers correlated with mouse-specific gene expression, suggesting that retroviruses may play a role in the evolution of placental development. Together with evidence that endogenous retroviruses have also provided crucial placental genes such as syncytin-1/-2, our work further underscores an unexpectedly intimate evolutionary relationship between retroviruses and the placenta.

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Chuong EB, Rumi MA, Soares MJ, Baker JC. Endogenous retroviruses function as species-specific enhancer elements in the placenta. Nature Genetics (2013) 45: 325-329. PMCID: PMC3789077

Chuong EB. Retroviruses facilitate the rapid evolution of the mammalian placenta. Bioessays (2013) 35:10 853-861

Chuong EB, Tong W, Hoekstra HE. Maternal-fetal conflict: Rapidly evolving proteins in the rodent placenta. Molecular Biology and Evolution (2010) vol. 27 (6):1221-1225.