Overview – Mechanisms of gene regulatory evolution
Our lab is broadly interested in the evolution of gene regulatory networks. Many important biological processes involve the coordinated expression of thousands of genes. It is now recognized that major evolutionary adaptations, such as changes in body structure, likely involve large-scale “rewiring” of gene regulatory networks.
How do changes in regulatory networks evolve? An intriguing answer may be the activity of transposons, which are “selfish” genetic sequences that serve no biological function other than to replicate itself within the genome. Yet, despite their parasitic nature, there is building evidence that transposons have played an important role in our evolution.
Our research seeks to understand the emerging role of transposons in the evolution of mammalian gene regulatory networks. We employ both computational and experimental approaches to decipher how transposons impact genome architecture and organismal biology. Our research is fundamentally interdisciplinary, and lies at the crossroads of diverse fields including genomics, epigenetics, evolution, immunity, and disease.
Some of our specific research directions are listed below.
Transposons and the evolution of immune regulatory networks
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.
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?
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. Yet, epigenetic repression is inherently reversible, and inappropriate transcriptional reactivation of transposons are common in many 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 be widespread. We are investigating these ideas by taking advantage of the massive wealth of genomic data being produced to compare diseased and healthy individuals, particularly in cancer.
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.
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.
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.