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Marsupial research reveals how mammalian embryos form

Researchers at the Francis Crick Institute have revealed insight into why embryos erase a key epigenetic mark during early development, suggesting this may have evolved to help form a placenta.

Epigenetic changes are modifications to DNA that don't change the underlying DNA sequence, like notes written on a recipe. They keep gene expression in check, affecting which genes are turned on or off.

A universally inherited epigenetic change among mammals, called DNA methylation, is wiped from the embryo before it implants, and is one of the earliest events in mammalian development. However, the reason for this dramatic erasure has remained mysterious.

Researchers speculated that this wiping event, known as DNA demethylation, must be needed for a specific step in mammalian development, such as activating the embryo's DNA or allowing embryonic cells to become different cell types. These processes happen at the same time in placental mammals like mice and humans, also known as eutherians, so until now it's been impossible to unpick the precise effects of this epigenetic process.

In a study today in Nature, the team at the Francis Crick Institute investigated, for the first time, epigenetic changes in embryos of a marsupial, which diverged from eutherians 160 million years ago. They focused on the opossum, which develops slower and in more discrete stages than eutherians, to outline which process DNA demethylation is needed for.

The researchers created a map of DNA methylation in opossum eggs, sperm and embryos, finding that levels of methylation in eggs and sperm were more similar to each other than they were in eutherians.

However, they found that, unlike eutherians, opossum embryos did not undergo a full wiping event. Instead, DNA methylation was retained in the early embryo, with loss occurring much later, and DNA demethylation was largely restricted to a specific supportive tissue called the trophectoderm, which becomes the marsupial placenta.

These findings show that demethylation isn't universally required for formation of an early mammalian embryo, because the opossum embryo develops without being fully wiped of this epigenetic mark. Instead, based on their findings, the team believe that wiping may have evolved specifically for the development of the placenta.

Bryony Leeke, former Ph.D. student in the Sex Chromosome Biology Laboratory at the Crick, together with co-first author and Principal Laboratory Research Scientist Wazeer Varsally, said, "Removing methylation specifically in the placenta allows expression of transposons, so-called 'jumping genes' which help modify when and where host genes are expressed. These modifications may contribute to the placenta being one of the most rapidly evolving organs in mammals."

James Turner, Principal Group Leader of the Sex Chromosome Biology Laboratory and senior author, said, "It was a big surprise that the universal wiping seen in eutherian mammals didn't happen in the opossum. In eutherians, the trophectoderm forms really early, so wiping the full embryonic structure might be helpful to allow any of these cells to become part of this supportive tissue.

"Working on marsupials continues to amaze and surprise us. They're often the odd one out, but it's this characteristic that means they reveal so much about biology in the more common mammals, including humans."