A copy-and-paste gene regulatory network

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Science  04 Mar 2016:
Vol. 351, Issue 6277, pp. 1029-1030
DOI: 10.1126/science.aaf2977

Changes in gene regulatory networks (GRNs) underlie many phenotypic differences between species. However, the mechanisms of GRN evolution are still being debated (15). Explaining how GRNs originate, diversify, and maintain their identities despite regulatory element turnover is essential for developing mechanistic explanations for the origin, diversification, and conservation of homologous characters between species. Among the major outstanding questions in GRN evolution is whether individual cis-regulatory elements arise de novo through the gradual accumulation of mutations that increase the regulatory potential of existing DNA or whether cis-regulatory elements originate more rapidly through concerted processes. On page 1083 of this issue, Chuong et al. provide evidence that concerted processes, involving endogenous retroviruses (ERVs), which are remarkably abundant in mammalian genomes, have contributed to the evolution of the regulatory systems that control the mammalian immune system (6).

Plug-and-play gene regulatory network formation.

The de novo model of GRN formation requires that each gene in the network (TG-1 to TG-3) independently evolve a new cis-regulatory element (CRE) that can bind to the same sets of transcription factors (red and blue circles). However, individual transcription factor binding sites may not be sufficient to activate target gene expression, requiring the evolution of additional binding sites for cooperating transcription factors or novel protein-protein interactions (PPIs) to recruit more transcription factors and cofactors. Alternatively, TEs can generate new regulatory networks by donating already functional cis-regulatory elements to neighboring genes.


Transposable element (TE)-mediated origination of cis-regulatory elements is an attractive alternative to the de novo appearance of such elements. TEs provide a mechanism to rapidly distribute nearly identical copies of regulatory elements across the genome that can respond to the same input signals (79) rather than requiring that each gene in a GRN evolve cis-regulatory elements capable of responding to the same stereotyped signals de novo (see the figure). The de novo origination model, for example, would require the independent evolution of the same transcription factor binding site(s) in many genes distributed across the genome, whereas TEs can donate the same sets of transcription factor binding sites to nearby genes upon their integration into the genome.

Although TE-mediated rewiring of GRNs provides a simple and straightforward model of gene regulatory evolution, and numerous cis-regulatory elements for individual genes in mammalian genomes are derived from TEs (10), few studies have demonstrated that TEs actually have globally rewired GRNs (11). Among the most notable barriers to developing mechanistic explanations for the role of TEs in the origin and diversification of GRNs is a lack of model networks that are both amenable to detailed functional studies and that evolve rapidly enough that TEs can be caught in the act of remodeling the regulatory landscape. The mammalian immune system is an ideal model in which to explore the molecular mechanisms that underlie GRN evolution because numerous genomic and experimental resources have been developed for mammals. In addition, immune responses evolve fast enough that evolutionary changes can occur between relatively closely related species, yet slow enough that the functional significance of TE-derived regulatory elements can be inferred and experimentally validated.

Proinflammatory cytokines, such as interferon-γ (IFNG), are essential signaling molecules in the innate immune response that are released upon infection and that regulate a battery of downstream immunity factors called IFN-stimulated genes (ISGs). ISGs are regulated by cis-regulatory elements containing binding sites for interferon regulatory factor (IRF) and signal transducer and activator of transcription (STAT) transcription factors that are activated by IFN signaling. Although the innate immune response is conserved as a process, the specific genes activated by IFNG signaling have diverged within mammals, potentially reflecting lineage-specific adaptations to host-pathogen interactions. Chuong et al. found that 27 TE families were enriched within IFNG-responsive cis-regulatory elements. Remarkably, 20 of these TE families originated from long terminal repeat (LTR) promoter regions of ERVs. These data suggest that many TE-derived IFNG-responsive cis-regulatory elements arose from ancient retroviral infections.

Previous studies have implicated ERVs in the genesis of cis-regulatory elements important for the evolution of mammalian pregnancy (12), placentation (13), and most notably the core regulatory networks in embryonic stem cells (14). ERVs are normally repressed in somatic cells by histone modifications and methylation, suggesting that ERVs escape silencing in some contexts, such as the placenta and embryonic stem cells, which appear to have pervasive expression of ERVs. Chuong et al., for example, speculate that IFNG-responsive cis-regulatory elements in LTRs are remnants of ancient retroviral enhancers that used host signaling to promote viral transcription and replication; thus, ERVs may have evolved to be derepressed upon IFNG stimulation. This conjecture suggests an answer to a nagging question: What is it about TEs that predisposes them to act as tissue-specific regulatory elements? In this case, ERVs may be predisposed to act as regulatory elements in IFNG-responsive cells because they already possess functional IRF and STAT binding sites. More generally, TEs may be biased in the kinds of transcription factor binding sites they contain because of their own biology, leading to domestication as regulatory elements in cell types that already express those transcription factors. Although more detailed experimental approaches will be required to reconstruct the exact mechanisms by which TEs rewire gene regulatory networks, the experimental framework provided by Chuong et al. will lead the way.


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