Gene regulation in transition

An in-depth analysis of a close relative of animals, Capsaspora owczarzaki, provides clues to the changes in gene regulation that occurred during the transition to multicellularity.

The origin of all animals, from humans to sponges and comb jellies, can be traced back to a major event in evolutionary history: the transition to multicellularity. This transition was no doubt shaped by environmental changes — such as rising oxygen levels — and the evolution of cells that could engulf other, smaller cells1. However, to fully understand what drove this seminal event, we must look to the genome. Writing in Cell, Sebé-Pedrós et al.2 report an investigation of gene regulation in a microscopic cousin of animals, Capsaspora owczarzaki. The study indicates that Capsaspora represents a transitional state in the evolution of gene-regulatory mechanisms, and provides a foundation for investigating how such mechanisms might have contributed to animal origins.

More than 600 million years ago, a series of genetic innovations allowed the progenitors of animals to exploit emerging environmental niches on a changing planet3. These progenitors cannot be studied directly, so how can we identify those genetic innovations that mattered most for animal origins? Most insights into pre-animal genomes have come from comparisons of extant animals and their close relatives, choanoflagellates and Capsaspora (Fig. 1). Contrary to expectation, these studies revealed that much of the animal genetic toolkit (including the genes that encode cell-adhesion proteins such as integrins and cadherins, and those for vital signalling proteins such as receptor tyrosine kinases) is also expressed in Capsaspora and choanoflagellates4, indicating that many 'animal' genes pre-date animal origins.

Figure 1: Evolution of gene-regulatory mechanisms.

Sebé-Pedrós et al.2 report that two transcription factors, Myc and Brachyury, control similar sets of genes in animals and in a close relative, Capsaspora owczarzaki. This indicates that key gene-regulatory networks evolved before the origin of animals (indicated by the blue line) and were later co-opted for animal development. By contrast, long-range gene-regulatory elements called enhancers are not found in Capsaspora, but have been found in Nematostella, an animal that branched off early in evolutionary history. Thus, enhancers might be animal-specific (time window over which the evolution of long-range gene regulation might have occurred is indicated in red). A full understanding of how the animal gene-regulatory landscape evolved will require analyses of other early-branching animals such as sponges and Ctenophora (comb jellies), and other close relatives of animals, such as Choanoflagellata, in which gene regulation has not yet been studied (marked *).

Of course, animals are more than the sum of their genes — it is the regulated expression of genes across space and time that helps to differentiate egg from embryo, leg from wing or bat from fly. In plants and fungi, as well as in animals, transcription factors drive the synthesis of messenger RNA by interacting with regulatory regions called promoters that are located close to their target genes. Proximal control of transcription clearly pre-dates animal origins and is probably vital for all cellular life.

By contrast, long-range transcriptional regulation by DNA sequences called enhancers, which can lie more than 10 kilobases from the genes they regulate, has so far been seen only in animals. Such regulation has been hypothesized to underlie the spatial and temporal coordination of cell differentiation that defines animal development5. But whether long-range enhancers are truly restricted to animals has been unclear, because they are often embedded in intricate transcriptional networks and can be difficult to detect.

To investigate how different modes of transcriptional regulation may have set the stage for animal origins, Sebé-Pedrós et al. established approaches for functional genomics in Capsaspora (functional genomics probes how dynamic interactions between proteins, RNA and the genome correlate with gene expression). Despite the fact that Capsaspora is a non-model organism, it offers several benefits for such a study: it is easily cultured in the laboratory; it transitions between unicellular and aggregative multicellular forms; and its genome encodes many transcription factors that are evolutionarily conserved in animals6.

The authors report that, despite its relative simplicity, Capsaspora expresses two transcription factors that are integral to animal development — Myc and Brachyury. In animals, Myc serves as a master regulator of cell proliferation. Brachyury controls a key developmental process called gastrulation: this produces the body's three major cell layers, and the protein subsequently mediates differentiation of one of these layers, the mesoderm. In animals, both Myc and Brachyury function by binding to enhancers to regulate the transcription of a network of downstream genes7,8. Remarkably, Sebé-Pedrós et al. found that these downstream gene networks are conserved in animals and Capsaspora.

Given that cell proliferation is a shared feature of Capsaspora and animals, the conservation of the Myc regulatory network in the two lineages may not be surprising. But it is surprising that Brachyury seems to regulate the same types of gene in animals and Capsaspora, despite the fact that Capsaspora neither gastrulates nor produces mesoderm. Just as genes that animals use for cell adhesion and signalling evolved in the progenitors of animals before being co-opted for different functions in a multicellular context, it now seems that some gene-regulatory networks pre-date animal origins and were recruited wholesale for the regulation of new developmental processes.

Co-option is not the whole story, however. Innovations at the level of genes (such as that encoding the animal-specific signalling protein Wnt) and gene regulation (such as enhancer sequences) might also have contributed to animal origins. In contrast to the expansive intergenic DNA and long-range enhancers found in most animal genomes, the Capsapsora genome is compact. Despite looking for signatures of long-range transcriptional regulation at several stages of Capsaspora's life cycle, Sebé-Pedrós et al. identified none.

Animals also seem to have evolved new classes of promoter. Three types of animal promoter have been identified9: type I and type III promoters regulate genes that act during distinct stages in development, whereas type II promoters direct ubiquitous gene expression. Sebé-Pedrós and colleagues detected type II promoters in Capsaspora, but not types I or III. Therefore, type I and III promoters might be animal innovations.

It will be exciting to explore what these findings mean for animal origins and early evolution. Future investigations into the thus-far-uncharacterized gene-regulatory landscapes of sponges, comb jellies (ctenophores) and choanoflagellates promise to help pinpoint how and when long-range enhancers and type I and III promoters first evolved. However, the evolutionary distance between these organisms and the model animals that form the basis of our understanding of animal gene regulation may render conserved molecular mechanisms unrecognizable by functional-genomic approaches. Moreover, other evolutionarily important gene-regulatory mechanisms may lie undiscovered in Capsaspora, choanoflagellates and animals that branched off early in the evolution of animals.

Fully reconstructing gene regulation in the progenitors of animals will require studies in diverse relatives, integrating modern functional genomics with forward and reverse genetics — which respectively reveal the genes responsible for a particular trait, and the changes brought about by disrupting the function of a particular gene. Fortunately, armed with the functional-genomics insights from this study, and the establishment of forward genetics in choanoflagellates10, this goal may be achieved in the not-too-distant future. Footnote 1


  1. 1.

    See all news & views


  1. 1

    Knoll, A. H. Annu. Rev. Earth Planet. Sci. 39, 217–239 (2011).

    ADS  CAS  Article  Google Scholar 

  2. 2

    Sebé-Pedrós, A. et al. Cell 165, 1224–1237 (2016).

    Article  Google Scholar 

  3. 3

    Erwin, D. H. Biol. J. Linn. Soc. 50, 255–274 (1993).

    Article  Google Scholar 

  4. 4

    Richter, D. J. & King, N. Annu. Rev. Genet. 47, 509–537 (2013).

    Article  Google Scholar 

  5. 5

    Levine, M., Cattoglio, C. & Tjian, R. Cell 157, 13–25 (2014).

    CAS  Article  Google Scholar 

  6. 6

    Sebé-Pedrós, A. et al. eLife 2, e01287 (2013).

    Article  Google Scholar 

  7. 7

    Lolas, M., Valenzuela, P. D. T., Tjian, R. & Liu, Z. Proc. Natl Acad. Sci. USA 111, 4478–4483 (2014).

    ADS  CAS  Article  Google Scholar 

  8. 8

    Hurlin, P. J. Cold Spring Harb. Perspect. Med. 3, a014332 (2013).

    Article  Google Scholar 

  9. 9

    Lenhard, B., Sandelin, A. & Carninci, P. Nature Rev. Genet. 13, 233–245 (2012).

    CAS  Article  Google Scholar 

  10. 10

    Levin, T. C., Greaney, A. J., Wetzel, L. & King, N. eLife 3, e04070 (2014).

    Article  Google Scholar 

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Correspondence to David S. Booth or Nicole King.

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Booth, D., King, N. Gene regulation in transition. Nature 534, 482–483 (2016). https://doi.org/10.1038/nature18447

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