One of the biggest quests in biology is understanding how every cell in an animal's body carries an identical genome yet still gives rise to a kaleidoscope of different cell types and tissues. A neuron doesn't look nor behave like a muscle cell but has the same DNA.
Researchers think it comes down to how cells allow different parts of the genome to be read. Controlling these permissions are regulatory elements, regions of the genome which switch genes on or off. A detailed overview of how they do this is largely restricted to a handful of classic model organisms like mice and fruit flies.
For the first time, researchers have created a map which explains how the genome gives rise to different cell types in the starlet sea anemone, Nematostella vectensis.
Sea anemones, together with jellyfish and corals, belong to a group of animals called cnidarians. These are among the earliest animals in evolutionary history, first appearing on Earth around half a billion years ago.
The study systematically dissects the "regulatory logic" that defines cell identity in the sea anemone Nematostella. Rather than describing cell types through genes the atlas describes the regulatory elements that builds and maintains them instead. The study offers a glimpse of what sequence information in the genome encodes for the concerted activity of these regulatory networks.
The map, published today in Nature Ecology and Evolution, allows for the comparison of cell types in a different way. Grouping cells by which genes are active helps classify cells by function. But surprisingly, grouping them by regulatory elements instead tell us their developmental history, explaining from which embryonic germ layer they originated during development. That insight opens the door to exploring how similar cell types can arise from different germ layer origins, not only in development, but also during evolution.
For example, the study looked at two types of muscle cells which look similar, contract in similar ways and use almost the same genes, despite originating from different embryonic layers. The atlas revealed the genes in these cells are controlled by completely different regulatory elements.
"Expression tells us what cells do, but regulatory DNA tells us where they come from, how they develop, and which germ layer they originate from," explains Dr. Marta Iglesias, postdoctoral researcher at the Centre for Genomic Regulation and co-first author of the study.
"Our work highlights the power of combining single-cell genomic readouts with deep learning sequence models to decode the regulatory information contained in these genomes" adds Dr. Anamaria Elek, postdoctoral researcher at the Centre for Genomic Regulation and co-first author of the study.
Cnidarians are among the earliest animals to have neurons and muscle cells, and they also feature a unique cell type called cnidocytes. These cells contain tiny, harpoon-like structures that are used to capture prey and defend against predators, as well as the stinging sensation we feel when we touch a jellyfish or sea anemone.
For evolution, gene regulation networks are a creative tool. It means new cell types and tissues can emerge from changing gene regulatory switches alone. This could make it easier for complex cell diversity to evolve, even early in animal history. The work lays the foundation for showing how the cell type which give jellyfish and anemones their characteristic sting emerged in the first place.
As the research community builds more atlases of regulatory networks in other animals in the tree of life, including species that lack cnidocytes, they can start asking what parts of that circuitry are ancient, what parts are new, and what changed as new cell types emerged.
"This study opens a whole new world of possibilities. Going forward, we will investigate animal cellular evolution by comparing genomic sequence information, and for the first time, we can do so systematically and at scale," says ICREA Research Professor Arnau Sebe-Pedrós at the Centre for Genomic Regulation in Barcelona.
The researchers built the map by studying 60,000 individual cells from the sea anemone's body. They obtained them from two different life stages, around 52,000 from whole adult animals and 7,000 from gastrula-stage embryos, an early moment in development when the basic body plan is still being set up. From that, they constructed a detailed catalogue of 112,728 regulatory elements.
The scale of the discovery is surprising, given Nematostella vectensis has a genome about 269 million DNA letters long. It substantially exceeds previous estimates and approaches the same number of regulatory elements reported in the fruit fly Drosophila, which has a similar genome size of around 180 million DNA letters, but is part of a lineage that didn't appear on Earth until hundreds of millions of years later.
The finding suggests the toolkit for genomic regulation in complex animals existed long before actual complex bodies did. The rules which let our neurons fire and muscles contract today were already in place many hundreds of millions of years ago in animals drifting in ancient seas.
