Our lab is broadly interested in the evolution of gene regulatory networks. Different cell types have the same genome but express different genes, and the coordination of many complex gene expression programs is fundamental to complex cellular life. 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 lie in the activity of selfish genetic parasites. Broadly known as “transposons”, species genomes are littered with parasitic genetic sequences that serve no biological function other than to selfishly replicate themselves within the genome. Yet, despite their parasitic nature, there is emerging evidence that transposons have played fundamentally important roles 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.
A few of our major research areas are detailed below.
1. 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.
Chuong EB, Elde NC*, Feschotte C*. Regulatory evolution of innate immunity through co-option of endogenous retroviruses. Science (2016)
Chuong EB, Elde NC, Feschotte C. Regulatory activities of transposable elements: from conflicts to benefits. Nature Reviews Genetics (2017)
2. 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, all organisms have evolved genomic defenses to repress transposons 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 transposons can cause havoc in the cell through a number of different mechanisms, including transposing into tumor suppressors, or inappropriately triggering autoimmune responses. Less well studied is their impact on host gene regulation, which could be extremely widespread. We are investigating these ideas by taking advantage of the massive wealth of genomic data being produced to profile the epigenetic basis of disease.
3. 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 thought of as a harmonious interaction between mother and offspring, a long-standing hypothesis proposes that there is an inherent conflict between parent and offspring, which are genetically distinct (David Haig, Robert Trivers). We are interested in studying placenta evolution from this “parasitic” point of view, in hopes of advancing our understanding of this relatively understudied organ.
Intriguingly, endogenous retroviruses are abundantly expressed in the placenta. We profiled placental enhancer landscapes between mouse and rat, uncovering hundreds of mouse-specific enhancers derived from a mouse-specific endogenous retroviruses. Together with evidence that endogenous retroviruses have also provided crucial placental genes such as syncytin-1/-2, our work is uncovering an unexpectedly intimate relationship between retroviruses and the evolution of the placenta.
Guernsey MW, Chuong EB, Cornelis G, Renfree MB*, Baker JC*. Molecular conservation of marsupial and eutherian placentation and lactation. eLIFE (2017)
Chuong EB, Rumi MA, Soares MJ, Baker JC. Endogenous retroviruses function as species-specific enhancer elements in the placenta. Nature Genetics (2013)
Chuong EB. Retroviruses facilitate the rapid evolution of the mammalian placenta. Bioessays (2013)
Chuong EB, Tong W, Hoekstra HE. Maternal-fetal conflict: Rapidly evolving proteins in the rodent placenta. Molecular Biology and Evolution (2010)