Overview – Mechanisms of gene regulatory evolution

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Regulatory landscapes defined by integrated epigenetic profiling

Biology has been historically focused on the function of protein-coding genes, but it is now widely appreciated that changes in non-coding regulatory DNA commonly underlie both adaptation and disease. Rather than change the protein, these changes change when and where a gene is expressed, sometimes with dramatic consequences.

The non-coding genome has been dubbed the “dark matter” of the genome or even “junk DNA”, but technological advancements in recent years have cast a high-power spotlight that has illuminated a genomic landscape of richly populated by regulatory elements. The research community has produced thousands of datasets profiling hundreds of different cell types, disease states, and human populations. Yet, our technical ability to map these landscapes has far outpaced our biological understanding of the regulatory genome. Many basic questions remain unanswered–how did these landscapes form? What evolutionary and molecular processes govern the “birth” and “death” of regulatory elements, and their divergence across species?

Our lab seeks to integrate comprehensive genomic analysis and hypothesis-driven experimental approaches to uncover the mechanisms that shape the regulatory genome. Our work is poised to gain fundamental insight into human evolution and disease. 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.